<?xml version="1.0" encoding="US-ASCII"?>
<!-- Generated by CompSci Transform (tm) - http://www.compsciresources.com -->
<!-- Created: Fri Mar 10 20:31:37 UTC 2023 -->
<linkbase xmlns="http://www.xbrl.org/2003/linkbase" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xsi:schemaLocation="http://www.xbrl.org/2003/linkbase http://www.xbrl.org/2003/xbrl-linkbase-2003-12-31.xsd" xmlns:xbrldt="http://xbrl.org/2005/xbrldt">
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ConsolidatedBalanceSheet" roleURI="http://www.optimizerx.com/role/ConsolidatedBalanceSheet"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ConsolidatedBalanceSheet_Parentheticals" roleURI="http://www.optimizerx.com/role/ConsolidatedBalanceSheet_Parentheticals"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ConsolidatedIncomeStatement" roleURI="http://www.optimizerx.com/role/ConsolidatedIncomeStatement"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ShareholdersEquityType2or3" roleURI="http://www.optimizerx.com/role/ShareholdersEquityType2or3"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ConsolidatedCashFlow" roleURI="http://www.optimizerx.com/role/ConsolidatedCashFlow"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_OrganizationandNatureofBusiness" roleURI="http://www.optimizerx.com/role/OrganizationandNatureofBusiness"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_SummaryofSignificantAccountingPolicies" roleURI="http://www.optimizerx.com/role/SummaryofSignificantAccountingPolicies"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_PrepaidExpenses" roleURI="http://www.optimizerx.com/role/PrepaidExpenses"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_PropertyandEquipment" roleURI="http://www.optimizerx.com/role/PropertyandEquipment"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_IntangibleAssets" roleURI="http://www.optimizerx.com/role/IntangibleAssets"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_DeferredRevenue" roleURI="http://www.optimizerx.com/role/DeferredRevenue"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_RelatedPartyTransactions" roleURI="http://www.optimizerx.com/role/RelatedPartyTransactions"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ContingentPurchasePrice" roleURI="http://www.optimizerx.com/role/ContingentPurchasePrice"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_StockholdersEquity" roleURI="http://www.optimizerx.com/role/StockholdersEquity"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_StockCompensation" roleURI="http://www.optimizerx.com/role/StockCompensation"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_Leases" roleURI="http://www.optimizerx.com/role/Leases"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_MajorCustomersandVendors" roleURI="http://www.optimizerx.com/role/MajorCustomersandVendors"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_IncomeTaxes" roleURI="http://www.optimizerx.com/role/IncomeTaxes"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_CommitmentsandContingentLiabilities" roleURI="http://www.optimizerx.com/role/CommitmentsandContingentLiabilities"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_RetirementPlan" roleURI="http://www.optimizerx.com/role/RetirementPlan"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_AccountingPoliciesByPolicy" roleURI="http://www.optimizerx.com/role/AccountingPoliciesByPolicy"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_SummaryofSignificantAccountingPoliciesTables" roleURI="http://www.optimizerx.com/role/SummaryofSignificantAccountingPoliciesTables"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_PrepaidExpensesTables" roleURI="http://www.optimizerx.com/role/PrepaidExpensesTables"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_PropertyandEquipmentTables" roleURI="http://www.optimizerx.com/role/PropertyandEquipmentTables"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_IntangibleAssetsTables" roleURI="http://www.optimizerx.com/role/IntangibleAssetsTables"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_DeferredRevenueTables" roleURI="http://www.optimizerx.com/role/DeferredRevenueTables"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ContingentPurchasePriceTables" roleURI="http://www.optimizerx.com/role/ContingentPurchasePriceTables"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_StockCompensationTables" roleURI="http://www.optimizerx.com/role/StockCompensationTables"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_LeasesTables" roleURI="http://www.optimizerx.com/role/LeasesTables"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_MajorCustomersandVendorsTables" roleURI="http://www.optimizerx.com/role/MajorCustomersandVendorsTables"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_IncomeTaxesTables" roleURI="http://www.optimizerx.com/role/IncomeTaxesTables"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ScheduleoffinancialassetsandliabilitiesmeasuredonarecurringbasisTable" roleURI="http://www.optimizerx.com/role/ScheduleoffinancialassetsandliabilitiesmeasuredonarecurringbasisTable"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ScheduleofchangesinfairvalueoftheCompanysLevel3financialinstrumentsTable" roleURI="http://www.optimizerx.com/role/ScheduleofchangesinfairvalueoftheCompanysLevel3financialinstrumentsTable"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ScheduleofrevenueisearnedfromlifesciencescompaniesTable" roleURI="http://www.optimizerx.com/role/ScheduleofrevenueisearnedfromlifesciencescompaniesTable"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ScheduleofexpecteddividendsTable" roleURI="http://www.optimizerx.com/role/ScheduleofexpecteddividendsTable"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ScheduleofweightedaveragesharesoutstandingandthebasicanddilutedearningspercommonshareTable" roleURI="http://www.optimizerx.com/role/ScheduleofweightedaveragesharesoutstandingandthebasicanddilutedearningspercommonshareTable"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ScheduleofprepaidexpensesTable" roleURI="http://www.optimizerx.com/role/ScheduleofprepaidexpensesTable"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ScheduleofpropertyandequipmentTable" roleURI="http://www.optimizerx.com/role/ScheduleofpropertyandequipmentTable"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ScheduleofintangibleassetsincludedontheconsolidatedbalancesheetTable" roleURI="http://www.optimizerx.com/role/ScheduleofintangibleassetsincludedontheconsolidatedbalancesheetTable"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ScheduleofintangiblesestimatedusefullivesTable" roleURI="http://www.optimizerx.com/role/ScheduleofintangiblesestimatedusefullivesTable"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ScheduleoffutureamortizationexpensesofintangiblesassetsTable" roleURI="http://www.optimizerx.com/role/ScheduleoffutureamortizationexpensesofintangiblesassetsTable"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ScheduleofdeferredrevenueTable" roleURI="http://www.optimizerx.com/role/ScheduleofdeferredrevenueTable"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ScheduleoffairvalueofcontingentpurchasepricepayableTable" roleURI="http://www.optimizerx.com/role/ScheduleoffairvalueofcontingentpurchasepricepayableTable"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ScheduleofoptionactivityTable" roleURI="http://www.optimizerx.com/role/ScheduleofoptionactivityTable"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ScheduleoftotalandvestedoptionsoutstandingTable" roleURI="http://www.optimizerx.com/role/ScheduleoftotalandvestedoptionsoutstandingTable"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ScheduleofnonvestedsharesTable" roleURI="http://www.optimizerx.com/role/ScheduleofnonvestedsharesTable"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ScheduleofrestrictedstockawardsTable" roleURI="http://www.optimizerx.com/role/ScheduleofrestrictedstockawardsTable"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ScheduleofleasecostTable" roleURI="http://www.optimizerx.com/role/ScheduleofleasecostTable"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ScheduleoffutureminimumleasepaymentsTable" roleURI="http://www.optimizerx.com/role/ScheduleoffutureminimumleasepaymentsTable"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ScheduleofcustomersaccountedpercentageofrevenueTable" roleURI="http://www.optimizerx.com/role/ScheduleofcustomersaccountedpercentageofrevenueTable"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ScheduleoffederalincometaxbenefitTable" roleURI="http://www.optimizerx.com/role/ScheduleoffederalincometaxbenefitTable"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ScheduleofdeferredtaxassetsTable" roleURI="http://www.optimizerx.com/role/ScheduleofdeferredtaxassetsTable"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_OrganizationandNatureofBusinessDetails" roleURI="http://www.optimizerx.com/role/OrganizationandNatureofBusinessDetails"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_SummaryofSignificantAccountingPoliciesDetails" roleURI="http://www.optimizerx.com/role/SummaryofSignificantAccountingPoliciesDetails"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_PropertyandEquipmentDetails" roleURI="http://www.optimizerx.com/role/PropertyandEquipmentDetails"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_IntangibleAssetsDetails" roleURI="http://www.optimizerx.com/role/IntangibleAssetsDetails"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_DeferredRevenueDetails" roleURI="http://www.optimizerx.com/role/DeferredRevenueDetails"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_RelatedPartyTransactionsDetails" roleURI="http://www.optimizerx.com/role/RelatedPartyTransactionsDetails"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_ContingentPurchasePriceDetails" roleURI="http://www.optimizerx.com/role/ContingentPurchasePriceDetails"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_StockholdersEquityDetails" roleURI="http://www.optimizerx.com/role/StockholdersEquityDetails"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_StockCompensationDetails" roleURI="http://www.optimizerx.com/role/StockCompensationDetails"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_LeasesDetails" roleURI="http://www.optimizerx.com/role/LeasesDetails"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_MajorCustomersandVendorsDetails" roleURI="http://www.optimizerx.com/role/MajorCustomersandVendorsDetails"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_IncomeTaxesDetails" roleURI="http://www.optimizerx.com/role/IncomeTaxesDetails"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_CommitmentsandContingentLiabilitiesDetails" roleURI="http://www.optimizerx.com/role/CommitmentsandContingentLiabilitiesDetails"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#oprx_r_RetirementPlanDetails" roleURI="http://www.optimizerx.com/role/RetirementPlanDetails"/>
  <roleRef xlink:type="simple" xlink:href="oprx-20211231.xsd#DocumentAndEntityInformation" roleURI="http://www.optimizerx.com/role/DocumentAndEntityInformation"/>
  <arcroleRef xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#dimension-default" arcroleURI="http://xbrl.org/int/dim/arcrole/dimension-default"/>
  <arcroleRef xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#dimension-domain" arcroleURI="http://xbrl.org/int/dim/arcrole/dimension-domain"/>
  <arcroleRef xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#hypercube-dimension" arcroleURI="http://xbrl.org/int/dim/arcrole/hypercube-dimension"/>
  <arcroleRef xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#domain-member" arcroleURI="http://xbrl.org/int/dim/arcrole/domain-member"/>
  <arcroleRef xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#all" arcroleURI="http://xbrl.org/int/dim/arcrole/all"/>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ConsolidatedBalanceSheet">
    <loc xlink:type="locator" xlink:label="us-gaap_StatementOfFinancialPositionAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StatementOfFinancialPositionAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_AssetsCurrentAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_AssetsCurrentAbstract"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfFinancialPositionAbstract" xlink:to="us-gaap_AssetsCurrentAbstract" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_CashAndCashEquivalentsAtCarryingValue" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CashAndCashEquivalentsAtCarryingValue"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AssetsCurrentAbstract" xlink:to="us-gaap_CashAndCashEquivalentsAtCarryingValue" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_AccountsReceivableNetCurrent" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_AccountsReceivableNetCurrent"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AssetsCurrentAbstract" xlink:to="us-gaap_AccountsReceivableNetCurrent" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_PrepaidExpenseCurrent" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PrepaidExpenseCurrent"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AssetsCurrentAbstract" xlink:to="us-gaap_PrepaidExpenseCurrent" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_AssetsCurrent" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_AssetsCurrent"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfFinancialPositionAbstract" xlink:to="us-gaap_AssetsCurrent" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentNet" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PropertyPlantAndEquipmentNet"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfFinancialPositionAbstract" xlink:to="us-gaap_PropertyPlantAndEquipmentNet" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_OtherAssetsAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OtherAssetsAbstract"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfFinancialPositionAbstract" xlink:to="us-gaap_OtherAssetsAbstract" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_Goodwill" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_Goodwill"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_OtherAssetsAbstract" xlink:to="us-gaap_Goodwill" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_TechnologyAssetsNet" xlink:href="oprx-20211231.xsd#oprx_TechnologyAssetsNet"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_OtherAssetsAbstract" xlink:to="oprx_TechnologyAssetsNet" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_PatentRightsNet" xlink:href="oprx-20211231.xsd#oprx_PatentRightsNet"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_OtherAssetsAbstract" xlink:to="oprx_PatentRightsNet" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_OperatingLeaseRightOfUseAsset" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OperatingLeaseRightOfUseAsset"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_OtherAssetsAbstract" xlink:to="us-gaap_OperatingLeaseRightOfUseAsset" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_OtherIntangibleAssetsNet" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OtherIntangibleAssetsNet"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_OtherAssetsAbstract" xlink:to="us-gaap_OtherIntangibleAssetsNet" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_OtherAssetsAndDeposits" xlink:href="oprx-20211231.xsd#oprx_OtherAssetsAndDeposits"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_OtherAssetsAbstract" xlink:to="oprx_OtherAssetsAndDeposits" order="5" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_OtherAssets" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OtherAssets"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfFinancialPositionAbstract" xlink:to="us-gaap_OtherAssets" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_Assets" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_Assets"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfFinancialPositionAbstract" xlink:to="us-gaap_Assets" order="5" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_LiabilitiesCurrentAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_LiabilitiesCurrentAbstract"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfFinancialPositionAbstract" xlink:to="us-gaap_LiabilitiesCurrentAbstract" order="6" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_AccountsPayableTradeCurrent" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_AccountsPayableTradeCurrent"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LiabilitiesCurrentAbstract" xlink:to="us-gaap_AccountsPayableTradeCurrent" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_AccruedLiabilitiesCurrent" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_AccruedLiabilitiesCurrent"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LiabilitiesCurrentAbstract" xlink:to="us-gaap_AccruedLiabilitiesCurrent" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_RevenueSharePayableCurrent" xlink:href="oprx-20211231.xsd#oprx_RevenueSharePayableCurrent"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LiabilitiesCurrentAbstract" xlink:to="oprx_RevenueSharePayableCurrent" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_OperatingLeaseLiabilityCurrent" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OperatingLeaseLiabilityCurrent"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LiabilitiesCurrentAbstract" xlink:to="us-gaap_OperatingLeaseLiabilityCurrent" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_CurrentPortionOfContingentPurchasePricePayable" xlink:href="oprx-20211231.xsd#oprx_CurrentPortionOfContingentPurchasePricePayable"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LiabilitiesCurrentAbstract" xlink:to="oprx_CurrentPortionOfContingentPurchasePricePayable" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_DeferredRevenueCurrent" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DeferredRevenueCurrent"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LiabilitiesCurrentAbstract" xlink:to="us-gaap_DeferredRevenueCurrent" order="5" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_LiabilitiesCurrent" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_LiabilitiesCurrent"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LiabilitiesCurrentAbstract" xlink:to="us-gaap_LiabilitiesCurrent" order="6" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_LiabilitiesNoncurrentAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_LiabilitiesNoncurrentAbstract"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfFinancialPositionAbstract" xlink:to="us-gaap_LiabilitiesNoncurrentAbstract" order="7" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_OperatingLeaseLiabilityNoncurrent" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OperatingLeaseLiabilityNoncurrent"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LiabilitiesNoncurrentAbstract" xlink:to="us-gaap_OperatingLeaseLiabilityNoncurrent" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_Liabilities" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_Liabilities"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfFinancialPositionAbstract" xlink:to="us-gaap_Liabilities" order="8" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_CommitmentsAndContingencies" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CommitmentsAndContingencies"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfFinancialPositionAbstract" xlink:to="us-gaap_CommitmentsAndContingencies" order="9" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_StockholdersEquityAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StockholdersEquityAbstract"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfFinancialPositionAbstract" xlink:to="us-gaap_StockholdersEquityAbstract" order="10" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_PreferredStockValue" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PreferredStockValue"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StockholdersEquityAbstract" xlink:to="us-gaap_PreferredStockValue" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_CommonStockValue" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CommonStockValue"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StockholdersEquityAbstract" xlink:to="us-gaap_CommonStockValue" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_AdditionalPaidInCapital" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_AdditionalPaidInCapital"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StockholdersEquityAbstract" xlink:to="us-gaap_AdditionalPaidInCapital" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_RetainedEarningsAccumulatedDeficit" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_RetainedEarningsAccumulatedDeficit"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StockholdersEquityAbstract" xlink:to="us-gaap_RetainedEarningsAccumulatedDeficit" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_StockholdersEquity" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StockholdersEquity"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfFinancialPositionAbstract" xlink:to="us-gaap_StockholdersEquity" order="11" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_LiabilitiesAndStockholdersEquity" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_LiabilitiesAndStockholdersEquity"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfFinancialPositionAbstract" xlink:to="us-gaap_LiabilitiesAndStockholdersEquity" order="12" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ConsolidatedBalanceSheet_Parentheticals">
    <loc xlink:type="locator" xlink:label="us-gaap_StatementOfFinancialPositionAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StatementOfFinancialPositionAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_PreferredStockParOrStatedValuePerShare" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PreferredStockParOrStatedValuePerShare"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfFinancialPositionAbstract" xlink:to="us-gaap_PreferredStockParOrStatedValuePerShare" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_PreferredStockSharesAuthorized" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PreferredStockSharesAuthorized"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfFinancialPositionAbstract" xlink:to="us-gaap_PreferredStockSharesAuthorized" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_PreferredStockSharesIssued" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PreferredStockSharesIssued"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfFinancialPositionAbstract" xlink:to="us-gaap_PreferredStockSharesIssued" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_PreferredStockSharesOutstanding" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PreferredStockSharesOutstanding"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfFinancialPositionAbstract" xlink:to="us-gaap_PreferredStockSharesOutstanding" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_CommonStockParOrStatedValuePerShare" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CommonStockParOrStatedValuePerShare"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfFinancialPositionAbstract" xlink:to="us-gaap_CommonStockParOrStatedValuePerShare" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_CommonStockSharesAuthorized" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CommonStockSharesAuthorized"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfFinancialPositionAbstract" xlink:to="us-gaap_CommonStockSharesAuthorized" order="5" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_CommonStockSharesIssued" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CommonStockSharesIssued"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfFinancialPositionAbstract" xlink:to="us-gaap_CommonStockSharesIssued" order="6" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_CommonStockSharesOutstanding" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CommonStockSharesOutstanding"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfFinancialPositionAbstract" xlink:to="us-gaap_CommonStockSharesOutstanding" order="7" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ConsolidatedIncomeStatement">
    <loc xlink:type="locator" xlink:label="us-gaap_IncomeStatementAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_IncomeStatementAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_Revenues" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_Revenues"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeStatementAbstract" xlink:to="us-gaap_Revenues" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_CostOfRevenue" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CostOfRevenue"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeStatementAbstract" xlink:to="us-gaap_CostOfRevenue" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_GrossProfit" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_GrossProfit"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeStatementAbstract" xlink:to="us-gaap_GrossProfit" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_OperatingExpensesAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OperatingExpensesAbstract"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeStatementAbstract" xlink:to="us-gaap_OperatingExpensesAbstract" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_AllocatedShareBasedCompensationExpense" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_AllocatedShareBasedCompensationExpense"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_OperatingExpensesAbstract" xlink:to="us-gaap_AllocatedShareBasedCompensationExpense" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_DepreciationAndAmortization" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DepreciationAndAmortization"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_OperatingExpensesAbstract" xlink:to="us-gaap_DepreciationAndAmortization" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_OtherGeneralAndAdministrativeExpense" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OtherGeneralAndAdministrativeExpense"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_OperatingExpensesAbstract" xlink:to="us-gaap_OtherGeneralAndAdministrativeExpense" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_OperatingExpenses" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OperatingExpenses"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeStatementAbstract" xlink:to="us-gaap_OperatingExpenses" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_OperatingIncomeLoss" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OperatingIncomeLoss"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeStatementAbstract" xlink:to="us-gaap_OperatingIncomeLoss" order="5" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_OtherIncomeAndExpensesAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OtherIncomeAndExpensesAbstract"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeStatementAbstract" xlink:to="us-gaap_OtherIncomeAndExpensesAbstract" order="6" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_InvestmentIncomeInterest" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_InvestmentIncomeInterest"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_OtherIncomeAndExpensesAbstract" xlink:to="us-gaap_InvestmentIncomeInterest" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_ChangeInFairValueOfContingentConsideration" xlink:href="oprx-20211231.xsd#oprx_ChangeInFairValueOfContingentConsideration"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_OtherIncomeAndExpensesAbstract" xlink:to="oprx_ChangeInFairValueOfContingentConsideration" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_OtherNonoperatingIncomeExpense" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OtherNonoperatingIncomeExpense"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeStatementAbstract" xlink:to="us-gaap_OtherNonoperatingIncomeExpense" order="7" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeStatementAbstract" xlink:to="us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" order="8" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_IncomeTaxExpenseBenefit" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_IncomeTaxExpenseBenefit"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeStatementAbstract" xlink:to="us-gaap_IncomeTaxExpenseBenefit" order="9" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_NetIncomeLoss" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_NetIncomeLoss"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeStatementAbstract" xlink:to="us-gaap_NetIncomeLoss" order="10" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_WeightedAverageNumberOfSharesOutstandingBasic" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_WeightedAverageNumberOfSharesOutstandingBasic"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeStatementAbstract" xlink:to="us-gaap_WeightedAverageNumberOfSharesOutstandingBasic" order="11" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeStatementAbstract" xlink:to="us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding" order="12" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_EarningsPerShareBasic" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_EarningsPerShareBasic"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeStatementAbstract" xlink:to="us-gaap_EarningsPerShareBasic" order="13" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_EarningsPerShareDiluted" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_EarningsPerShareDiluted"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeStatementAbstract" xlink:to="us-gaap_EarningsPerShareDiluted" order="14" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ShareholdersEquityType2or3">
    <loc xlink:type="locator" xlink:label="us-gaap_StatementLineItems" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StatementLineItems"/>
    <loc xlink:type="locator" xlink:label="us-gaap_StatementTable" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StatementTable"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StatementTable" order="0" xbrldt:contextElement="segment" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_StatementEquityComponentsAxis" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StatementEquityComponentsAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_StatementTable" xlink:to="us-gaap_StatementEquityComponentsAxis" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_EquityComponentDomain" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_EquityComponentDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_StatementEquityComponentsAxis" xlink:to="us-gaap_EquityComponentDomain" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_EquityComponentDomain_0" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_EquityComponentDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_StatementEquityComponentsAxis" xlink:to="us-gaap_EquityComponentDomain_0" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_CommonStockMember" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CommonStockMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EquityComponentDomain" xlink:to="us-gaap_CommonStockMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_AdditionalPaidInCapitalMember" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_AdditionalPaidInCapitalMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EquityComponentDomain" xlink:to="us-gaap_AdditionalPaidInCapitalMember" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_RetainedEarningsMember" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_RetainedEarningsMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EquityComponentDomain" xlink:to="us-gaap_RetainedEarningsMember" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_StockholdersEquity" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StockholdersEquity"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StockholdersEquity" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_SharesOutstanding" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SharesOutstanding"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_SharesOutstanding" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationAndExerciseOfStockOptions" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationAndExerciseOfStockOptions"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationAndExerciseOfStockOptions" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_StockbasedCompensationExpenseOptions" xlink:href="oprx-20211231.xsd#oprx_StockbasedCompensationExpenseOptions"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationAndExerciseOfStockOptions" xlink:to="oprx_StockbasedCompensationExpenseOptions" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_StockIssuedDuringPeriodValueRestrictedStockAwardNetOfForfeitures" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StockIssuedDuringPeriodValueRestrictedStockAwardNetOfForfeitures"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationAndExerciseOfStockOptions" xlink:to="us-gaap_StockIssuedDuringPeriodValueRestrictedStockAwardNetOfForfeitures" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_StockIssuedDuringPeriodValueRestrictedStockAwardNetOfForfeituresShares" xlink:href="oprx-20211231.xsd#oprx_StockIssuedDuringPeriodValueRestrictedStockAwardNetOfForfeituresShares"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationAndExerciseOfStockOptions" xlink:to="oprx_StockIssuedDuringPeriodValueRestrictedStockAwardNetOfForfeituresShares" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_IssuanceOfCommonStockAbstract0" xlink:href="oprx-20211231.xsd#oprx_IssuanceOfCommonStockAbstract0"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="oprx_IssuanceOfCommonStockAbstract0" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_StockIssuedDuringPeriodValueIssuedForServices" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StockIssuedDuringPeriodValueIssuedForServices"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodValueIssuedForServices" order="5" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_StockIssuedDuringPeriodSharesIssuedForServices" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StockIssuedDuringPeriodSharesIssuedForServices"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodSharesIssuedForServices" order="6" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_StockIssuedDuringPeriodValueStockOptionsExercised" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StockIssuedDuringPeriodValueStockOptionsExercised"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodValueStockOptionsExercised" order="7" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_StockIssuedDuringPeriodSharesStockOptionsExercised" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StockIssuedDuringPeriodSharesStockOptionsExercised"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodSharesStockOptionsExercised" order="8" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_IssuanceOfCommonStockForContingentPurchasePriceAndEscrowHoldBack" xlink:href="oprx-20211231.xsd#oprx_IssuanceOfCommonStockForContingentPurchasePriceAndEscrowHoldBack"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StockIssuedDuringPeriodSharesStockOptionsExercised" xlink:to="oprx_IssuanceOfCommonStockForContingentPurchasePriceAndEscrowHoldBack" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_IssuanceOfCommonStockForContingentPurchasePriceAndEscrowHoldBackShares" xlink:href="oprx-20211231.xsd#oprx_IssuanceOfCommonStockForContingentPurchasePriceAndEscrowHoldBackShares"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StockIssuedDuringPeriodSharesStockOptionsExercised" xlink:to="oprx_IssuanceOfCommonStockForContingentPurchasePriceAndEscrowHoldBackShares" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_PublicOfferingOfCommonSharesNetOfOfferingCosts" xlink:href="oprx-20211231.xsd#oprx_PublicOfferingOfCommonSharesNetOfOfferingCosts"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="oprx_PublicOfferingOfCommonSharesNetOfOfferingCosts" order="9" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_PublicOfferingOfCommonSharesNetOfOfferingCostsinShares" xlink:href="oprx-20211231.xsd#oprx_PublicOfferingOfCommonSharesNetOfOfferingCostsinShares"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="oprx_PublicOfferingOfCommonSharesNetOfOfferingCostsinShares" order="10" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ProfitLoss" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ProfitLoss"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_ProfitLoss" order="11" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ConsolidatedCashFlow">
    <loc xlink:type="locator" xlink:label="us-gaap_StatementOfCashFlowsAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StatementOfCashFlowsAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfCashFlowsAbstract" xlink:to="us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_NetIncomeLoss" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_NetIncomeLoss"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract" xlink:to="us-gaap_NetIncomeLoss" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfCashFlowsAbstract" xlink:to="us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_DepreciationAndAmortizationValue" xlink:href="oprx-20211231.xsd#oprx_DepreciationAndAmortizationValue"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract" xlink:to="oprx_DepreciationAndAmortizationValue" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_OtherNoncashExpense" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OtherNoncashExpense"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract" xlink:to="us-gaap_OtherNoncashExpense" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_ProvisionForLossOnAccountsReceivable" xlink:href="oprx-20211231.xsd#oprx_ProvisionForLossOnAccountsReceivable"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract" xlink:to="oprx_ProvisionForLossOnAccountsReceivable" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_StockIssuedForBoardService" xlink:href="oprx-20211231.xsd#oprx_StockIssuedForBoardService"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract" xlink:to="oprx_StockIssuedForBoardService" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_ChangeInFairValueOfContingentConsideration" xlink:href="oprx-20211231.xsd#oprx_ChangeInFairValueOfContingentConsideration"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract" xlink:to="oprx_ChangeInFairValueOfContingentConsideration" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_IncreaseDecreaseInOperatingCapitalAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_IncreaseDecreaseInOperatingCapitalAbstract"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfCashFlowsAbstract" xlink:to="us-gaap_IncreaseDecreaseInOperatingCapitalAbstract" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_IncreaseDecreaseInAccountsReceivable" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_IncreaseDecreaseInAccountsReceivable"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncreaseDecreaseInOperatingCapitalAbstract" xlink:to="us-gaap_IncreaseDecreaseInAccountsReceivable" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_IncreaseDecreaseInPrepaidDeferredExpenseAndOtherAssets" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_IncreaseDecreaseInPrepaidDeferredExpenseAndOtherAssets"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncreaseDecreaseInOperatingCapitalAbstract" xlink:to="us-gaap_IncreaseDecreaseInPrepaidDeferredExpenseAndOtherAssets" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_IncreaseDecreaseInAccountsPayable" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_IncreaseDecreaseInAccountsPayable"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncreaseDecreaseInOperatingCapitalAbstract" xlink:to="us-gaap_IncreaseDecreaseInAccountsPayable" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_IncreaseDecreaseInRevenueSharePayable" xlink:href="oprx-20211231.xsd#oprx_IncreaseDecreaseInRevenueSharePayable"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncreaseDecreaseInOperatingCapitalAbstract" xlink:to="oprx_IncreaseDecreaseInRevenueSharePayable" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_IncreaseDecreaseInOtherAccountsPayableAndAccruedLiabilities" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_IncreaseDecreaseInOtherAccountsPayableAndAccruedLiabilities"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncreaseDecreaseInOperatingCapitalAbstract" xlink:to="us-gaap_IncreaseDecreaseInOtherAccountsPayableAndAccruedLiabilities" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_IncreaseDecreaseInOtherOperatingLiabilities" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_IncreaseDecreaseInOtherOperatingLiabilities"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncreaseDecreaseInOperatingCapitalAbstract" xlink:to="us-gaap_IncreaseDecreaseInOtherOperatingLiabilities" order="5" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_IncreaseDecreaseInDeferredRevenue" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_IncreaseDecreaseInDeferredRevenue"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncreaseDecreaseInOperatingCapitalAbstract" xlink:to="us-gaap_IncreaseDecreaseInDeferredRevenue" order="6" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_NetCashProvidedByUsedInOperatingActivities"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncreaseDecreaseInOperatingCapitalAbstract" xlink:to="us-gaap_NetCashProvidedByUsedInOperatingActivities" order="7" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfCashFlowsAbstract" xlink:to="us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_PaymentsToAcquirePropertyPlantAndEquipment" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PaymentsToAcquirePropertyPlantAndEquipment"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract" xlink:to="us-gaap_PaymentsToAcquirePropertyPlantAndEquipment" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_PaymentsToAcquireIntangibleAssets" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PaymentsToAcquireIntangibleAssets"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract" xlink:to="us-gaap_PaymentsToAcquireIntangibleAssets" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_PaymentsToDevelopSoftware" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PaymentsToDevelopSoftware"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract" xlink:to="us-gaap_PaymentsToDevelopSoftware" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_NetCashProvidedByUsedInInvestingActivities" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_NetCashProvidedByUsedInInvestingActivities"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract" xlink:to="us-gaap_NetCashProvidedByUsedInInvestingActivities" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfCashFlowsAbstract" xlink:to="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ProceedsFromIssuanceOfCommonStock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ProceedsFromIssuanceOfCommonStock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract" xlink:to="us-gaap_ProceedsFromIssuanceOfCommonStock" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ProceedsFromStockOptionsExercised" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ProceedsFromStockOptionsExercised"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract" xlink:to="us-gaap_ProceedsFromStockOptionsExercised" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_PaymentForContingentConsiderationLiabilityFinancingActivities" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PaymentForContingentConsiderationLiabilityFinancingActivities"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract" xlink:to="us-gaap_PaymentForContingentConsiderationLiabilityFinancingActivities" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_NetCashProvidedByUsedInFinancingActivities"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract" xlink:to="us-gaap_NetCashProvidedByUsedInFinancingActivities" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfCashFlowsAbstract" xlink:to="us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect" order="5" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfCashFlowsAbstract" xlink:to="us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents" order="6" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_SupplementalCashFlowInformationAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SupplementalCashFlowInformationAbstract"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfCashFlowsAbstract" xlink:to="us-gaap_SupplementalCashFlowInformationAbstract" order="7" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_InterestPaidNet" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_InterestPaidNet"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SupplementalCashFlowInformationAbstract" xlink:to="us-gaap_InterestPaidNet" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_IncomeTaxesPaid" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_IncomeTaxesPaid"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SupplementalCashFlowInformationAbstract" xlink:to="us-gaap_IncomeTaxesPaid" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_NonCashInvestingAndFinancingActivitiesAbstract" xlink:href="oprx-20211231.xsd#oprx_NonCashInvestingAndFinancingActivitiesAbstract"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementOfCashFlowsAbstract" xlink:to="oprx_NonCashInvestingAndFinancingActivitiesAbstract" order="8" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_StockIssued1" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StockIssued1"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_NonCashInvestingAndFinancingActivitiesAbstract" xlink:to="us-gaap_StockIssued1" order="0" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/OrganizationandNatureofBusiness">
    <loc xlink:type="locator" xlink:label="us-gaap_OrganizationConsolidationAndPresentationOfFinancialStatementsAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OrganizationConsolidationAndPresentationOfFinancialStatementsAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_OrganizationConsolidationAndPresentationOfFinancialStatementsAbstract" xlink:to="us-gaap_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureTextBlock" order="0" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/SummaryofSignificantAccountingPolicies">
    <loc xlink:type="locator" xlink:label="us-gaap_AccountingPoliciesAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_AccountingPoliciesAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_SignificantAccountingPoliciesTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SignificantAccountingPoliciesTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccountingPoliciesAbstract" xlink:to="us-gaap_SignificantAccountingPoliciesTextBlock" order="0" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/PrepaidExpenses">
    <loc xlink:type="locator" xlink:label="oprx_PrepaidExpensesAbstract" xlink:href="oprx-20211231.xsd#oprx_PrepaidExpensesAbstract"/>
    <loc xlink:type="locator" xlink:label="oprx_PrepaidExpensesTextBlock" xlink:href="oprx-20211231.xsd#oprx_PrepaidExpensesTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_PrepaidExpensesAbstract" xlink:to="oprx_PrepaidExpensesTextBlock" order="0" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/PropertyandEquipment">
    <loc xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PropertyPlantAndEquipmentAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentDisclosureTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PropertyPlantAndEquipmentDisclosureTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PropertyPlantAndEquipmentAbstract" xlink:to="us-gaap_PropertyPlantAndEquipmentDisclosureTextBlock" order="0" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/IntangibleAssets">
    <loc xlink:type="locator" xlink:label="us-gaap_GoodwillAndIntangibleAssetsDisclosureAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_GoodwillAndIntangibleAssetsDisclosureAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_IntangibleAssetsDisclosureTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_IntangibleAssetsDisclosureTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_GoodwillAndIntangibleAssetsDisclosureAbstract" xlink:to="us-gaap_IntangibleAssetsDisclosureTextBlock" order="0" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/DeferredRevenue">
    <loc xlink:type="locator" xlink:label="us-gaap_DisclosureTextBlockAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DisclosureTextBlockAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_DeferredRevenueDisclosureTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DeferredRevenueDisclosureTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DisclosureTextBlockAbstract" xlink:to="us-gaap_DeferredRevenueDisclosureTextBlock" order="0" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/RelatedPartyTransactions">
    <loc xlink:type="locator" xlink:label="us-gaap_RelatedPartyTransactionsAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_RelatedPartyTransactionsAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_RelatedPartyTransactionsDisclosureTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_RelatedPartyTransactionsDisclosureTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_RelatedPartyTransactionsAbstract" xlink:to="us-gaap_RelatedPartyTransactionsDisclosureTextBlock" order="0" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ContingentPurchasePrice">
    <loc xlink:type="locator" xlink:label="us-gaap_LossContingencyAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_LossContingencyAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_LossContingencyDisclosures" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_LossContingencyDisclosures"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LossContingencyAbstract" xlink:to="us-gaap_LossContingencyDisclosures" order="0" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/StockholdersEquity">
    <loc xlink:type="locator" xlink:label="us-gaap_StockholdersEquityNoteAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StockholdersEquityNoteAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_StockholdersEquityNoteDisclosureTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StockholdersEquityNoteDisclosureTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StockholdersEquityNoteAbstract" xlink:to="us-gaap_StockholdersEquityNoteDisclosureTextBlock" order="0" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/StockCompensation">
    <loc xlink:type="locator" xlink:label="us-gaap_DisclosureOfCompensationRelatedCostsSharebasedPaymentsAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DisclosureOfCompensationRelatedCostsSharebasedPaymentsAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_DisclosureOfCompensationRelatedCostsShareBasedPaymentsTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DisclosureOfCompensationRelatedCostsShareBasedPaymentsTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DisclosureOfCompensationRelatedCostsSharebasedPaymentsAbstract" xlink:to="us-gaap_DisclosureOfCompensationRelatedCostsShareBasedPaymentsTextBlock" order="0" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/Leases">
    <loc xlink:type="locator" xlink:label="us-gaap_LeasesAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_LeasesAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_LesseeOperatingLeasesTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_LesseeOperatingLeasesTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LeasesAbstract" xlink:to="us-gaap_LesseeOperatingLeasesTextBlock" order="0" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/MajorCustomersandVendors">
    <loc xlink:type="locator" xlink:label="us-gaap_RisksAndUncertaintiesAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_RisksAndUncertaintiesAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ConcentrationRiskDisclosureTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ConcentrationRiskDisclosureTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_RisksAndUncertaintiesAbstract" xlink:to="us-gaap_ConcentrationRiskDisclosureTextBlock" order="0" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/IncomeTaxes">
    <loc xlink:type="locator" xlink:label="us-gaap_IncomeTaxDisclosureAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_IncomeTaxDisclosureAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_IncomeTaxDisclosureTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_IncomeTaxDisclosureTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeTaxDisclosureAbstract" xlink:to="us-gaap_IncomeTaxDisclosureTextBlock" order="0" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/CommitmentsandContingentLiabilities">
    <loc xlink:type="locator" xlink:label="us-gaap_CommitmentsAndContingenciesDisclosureAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CommitmentsAndContingenciesDisclosureAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_CommitmentsAndContingenciesDisclosureTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CommitmentsAndContingenciesDisclosureTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_CommitmentsAndContingenciesDisclosureAbstract" xlink:to="us-gaap_CommitmentsAndContingenciesDisclosureTextBlock" order="0" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/RetirementPlan">
    <loc xlink:type="locator" xlink:label="us-gaap_CompensationAndRetirementDisclosureAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CompensationAndRetirementDisclosureAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_PensionAndOtherPostretirementBenefitsDisclosureTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PensionAndOtherPostretirementBenefitsDisclosureTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_CompensationAndRetirementDisclosureAbstract" xlink:to="us-gaap_PensionAndOtherPostretirementBenefitsDisclosureTextBlock" order="0" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/AccountingPoliciesByPolicy">
    <loc xlink:type="locator" xlink:label="us-gaap_AccountingPoliciesAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_AccountingPoliciesAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_BasisOfAccountingPolicyPolicyTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_BasisOfAccountingPolicyPolicyTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccountingPoliciesAbstract" xlink:to="us-gaap_BasisOfAccountingPolicyPolicyTextBlock" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_UseOfEstimates" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_UseOfEstimates"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccountingPoliciesAbstract" xlink:to="us-gaap_UseOfEstimates" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ConsolidationPolicyTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ConsolidationPolicyTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccountingPoliciesAbstract" xlink:to="us-gaap_ConsolidationPolicyTextBlock" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_PriorPeriodReclassificationAdjustmentDescription" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PriorPeriodReclassificationAdjustmentDescription"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccountingPoliciesAbstract" xlink:to="us-gaap_PriorPeriodReclassificationAdjustmentDescription" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ForeignCurrencyTransactionsAndTranslationsPolicyTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ForeignCurrencyTransactionsAndTranslationsPolicyTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccountingPoliciesAbstract" xlink:to="us-gaap_ForeignCurrencyTransactionsAndTranslationsPolicyTextBlock" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_CashAndCashEquivalentsPolicyTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CashAndCashEquivalentsPolicyTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccountingPoliciesAbstract" xlink:to="us-gaap_CashAndCashEquivalentsPolicyTextBlock" order="5" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FairValueMeasurementPolicyPolicyTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FairValueMeasurementPolicyPolicyTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccountingPoliciesAbstract" xlink:to="us-gaap_FairValueMeasurementPolicyPolicyTextBlock" order="6" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ReceivablesTradeAndOtherAccountsReceivableAllowanceForDoubtfulAccountsPolicy" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ReceivablesTradeAndOtherAccountsReceivableAllowanceForDoubtfulAccountsPolicy"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccountingPoliciesAbstract" xlink:to="us-gaap_ReceivablesTradeAndOtherAccountsReceivableAllowanceForDoubtfulAccountsPolicy" order="7" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentPolicyTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PropertyPlantAndEquipmentPolicyTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccountingPoliciesAbstract" xlink:to="us-gaap_PropertyPlantAndEquipmentPolicyTextBlock" order="8" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_GoodwillAndIntangibleAssetsPolicyTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_GoodwillAndIntangibleAssetsPolicyTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccountingPoliciesAbstract" xlink:to="us-gaap_GoodwillAndIntangibleAssetsPolicyTextBlock" order="9" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_GoodwillAndIntangibleAssetsGoodwillPolicy" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_GoodwillAndIntangibleAssetsGoodwillPolicy"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccountingPoliciesAbstract" xlink:to="us-gaap_GoodwillAndIntangibleAssetsGoodwillPolicy" order="10" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_RevenueRecognitionPolicyTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_RevenueRecognitionPolicyTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccountingPoliciesAbstract" xlink:to="us-gaap_RevenueRecognitionPolicyTextBlock" order="11" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_CostOfRevenuesPolicyPolicyTextBlock" xlink:href="oprx-20211231.xsd#oprx_CostOfRevenuesPolicyPolicyTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccountingPoliciesAbstract" xlink:to="oprx_CostOfRevenuesPolicyPolicyTextBlock" order="12" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_IncomeTaxPolicyTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_IncomeTaxPolicyTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccountingPoliciesAbstract" xlink:to="us-gaap_IncomeTaxPolicyTextBlock" order="13" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ConcentrationRiskCreditRisk" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ConcentrationRiskCreditRisk"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccountingPoliciesAbstract" xlink:to="us-gaap_ConcentrationRiskCreditRisk" order="14" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ResearchAndDevelopmentExpensePolicy" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ResearchAndDevelopmentExpensePolicy"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccountingPoliciesAbstract" xlink:to="us-gaap_ResearchAndDevelopmentExpensePolicy" order="15" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationOptionAndIncentivePlansPolicy" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationOptionAndIncentivePlansPolicy"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccountingPoliciesAbstract" xlink:to="us-gaap_ShareBasedCompensationOptionAndIncentivePlansPolicy" order="16" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_EarningsPerSharePolicyTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_EarningsPerSharePolicyTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccountingPoliciesAbstract" xlink:to="us-gaap_EarningsPerSharePolicyTextBlock" order="17" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ImpairmentOrDisposalOfLongLivedAssetsPolicyTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ImpairmentOrDisposalOfLongLivedAssetsPolicyTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccountingPoliciesAbstract" xlink:to="us-gaap_ImpairmentOrDisposalOfLongLivedAssetsPolicyTextBlock" order="18" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_SegmentReportingPolicyPolicyTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SegmentReportingPolicyPolicyTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccountingPoliciesAbstract" xlink:to="us-gaap_SegmentReportingPolicyPolicyTextBlock" order="19" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_NewAccountingPronouncementsPolicyPolicyTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_NewAccountingPronouncementsPolicyPolicyTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccountingPoliciesAbstract" xlink:to="us-gaap_NewAccountingPronouncementsPolicyPolicyTextBlock" order="20" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_NotYetAdoptedPolicyPolicyTextBlock" xlink:href="oprx-20211231.xsd#oprx_NotYetAdoptedPolicyPolicyTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccountingPoliciesAbstract" xlink:to="oprx_NotYetAdoptedPolicyPolicyTextBlock" order="21" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/SummaryofSignificantAccountingPoliciesTables">
    <loc xlink:type="locator" xlink:label="us-gaap_AccountingPoliciesAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_AccountingPoliciesAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisValuationTechniquesTableTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisValuationTechniquesTableTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccountingPoliciesAbstract" xlink:to="us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisValuationTechniquesTableTextBlock" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FairValueLiabilitiesMeasuredOnRecurringBasisUnobservableInputReconciliationTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FairValueLiabilitiesMeasuredOnRecurringBasisUnobservableInputReconciliationTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccountingPoliciesAbstract" xlink:to="us-gaap_FairValueLiabilitiesMeasuredOnRecurringBasisUnobservableInputReconciliationTextBlock" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ScheduleOfRevenueByMajorCustomersByReportingSegmentsTableTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ScheduleOfRevenueByMajorCustomersByReportingSegmentsTableTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccountingPoliciesAbstract" xlink:to="us-gaap_ScheduleOfRevenueByMajorCustomersByReportingSegmentsTableTextBlock" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_DisclosureOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DisclosureOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccountingPoliciesAbstract" xlink:to="us-gaap_DisclosureOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTextBlock" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ScheduleOfEarningsPerShareBasicAndDilutedTableTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ScheduleOfEarningsPerShareBasicAndDilutedTableTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccountingPoliciesAbstract" xlink:to="us-gaap_ScheduleOfEarningsPerShareBasicAndDilutedTableTextBlock" order="4" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/PrepaidExpensesTables">
    <loc xlink:type="locator" xlink:label="oprx_PrepaidExpensesAbstract" xlink:href="oprx-20211231.xsd#oprx_PrepaidExpensesAbstract"/>
    <loc xlink:type="locator" xlink:label="oprx_ScheduleOfPrepaidExpensesTableTextBlock" xlink:href="oprx-20211231.xsd#oprx_ScheduleOfPrepaidExpensesTableTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_PrepaidExpensesAbstract" xlink:to="oprx_ScheduleOfPrepaidExpensesTableTextBlock" order="0" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/PropertyandEquipmentTables">
    <loc xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PropertyPlantAndEquipmentAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PropertyPlantAndEquipmentTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PropertyPlantAndEquipmentAbstract" xlink:to="us-gaap_PropertyPlantAndEquipmentTextBlock" order="0" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/IntangibleAssetsTables">
    <loc xlink:type="locator" xlink:label="us-gaap_GoodwillAndIntangibleAssetsDisclosureAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_GoodwillAndIntangibleAssetsDisclosureAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ScheduleOfIntangibleAssetsAndGoodwillTableTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ScheduleOfIntangibleAssetsAndGoodwillTableTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_GoodwillAndIntangibleAssetsDisclosureAbstract" xlink:to="us-gaap_ScheduleOfIntangibleAssetsAndGoodwillTableTextBlock" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ScheduleOfFiniteLivedIntangibleAssetsTableTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ScheduleOfFiniteLivedIntangibleAssetsTableTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_GoodwillAndIntangibleAssetsDisclosureAbstract" xlink:to="us-gaap_ScheduleOfFiniteLivedIntangibleAssetsTableTextBlock" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_ScheduleOfFutureAmortizationExpensesOfIntangiblesAssetsTableTextBlock" xlink:href="oprx-20211231.xsd#oprx_ScheduleOfFutureAmortizationExpensesOfIntangiblesAssetsTableTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_GoodwillAndIntangibleAssetsDisclosureAbstract" xlink:to="oprx_ScheduleOfFutureAmortizationExpensesOfIntangiblesAssetsTableTextBlock" order="2" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/DeferredRevenueTables">
    <loc xlink:type="locator" xlink:label="us-gaap_DisclosureTextBlockAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DisclosureTextBlockAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_DeferredRevenueByArrangementDisclosureTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DeferredRevenueByArrangementDisclosureTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DisclosureTextBlockAbstract" xlink:to="us-gaap_DeferredRevenueByArrangementDisclosureTextBlock" order="0" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ContingentPurchasePriceTables">
    <loc xlink:type="locator" xlink:label="us-gaap_LossContingencyAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_LossContingencyAbstract"/>
    <loc xlink:type="locator" xlink:label="oprx_FairValueOfContingentPurchasePricePayablesTableTextBlock" xlink:href="oprx-20211231.xsd#oprx_FairValueOfContingentPurchasePricePayablesTableTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LossContingencyAbstract" xlink:to="oprx_FairValueOfContingentPurchasePricePayablesTableTextBlock" order="0" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/StockCompensationTables">
    <loc xlink:type="locator" xlink:label="us-gaap_DisclosureOfCompensationRelatedCostsSharebasedPaymentsAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DisclosureOfCompensationRelatedCostsSharebasedPaymentsAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ScheduleOfShareBasedCompensationStockOptionsActivityTableTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ScheduleOfShareBasedCompensationStockOptionsActivityTableTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DisclosureOfCompensationRelatedCostsSharebasedPaymentsAbstract" xlink:to="us-gaap_ScheduleOfShareBasedCompensationStockOptionsActivityTableTextBlock" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ScheduleOfShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ScheduleOfShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DisclosureOfCompensationRelatedCostsSharebasedPaymentsAbstract" xlink:to="us-gaap_ScheduleOfShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeTextBlock" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ScheduleOfNonvestedShareActivityTableTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ScheduleOfNonvestedShareActivityTableTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DisclosureOfCompensationRelatedCostsSharebasedPaymentsAbstract" xlink:to="us-gaap_ScheduleOfNonvestedShareActivityTableTextBlock" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ScheduleOfNonvestedRestrictedStockUnitsActivityTableTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ScheduleOfNonvestedRestrictedStockUnitsActivityTableTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DisclosureOfCompensationRelatedCostsSharebasedPaymentsAbstract" xlink:to="us-gaap_ScheduleOfNonvestedRestrictedStockUnitsActivityTableTextBlock" order="3" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/LeasesTables">
    <loc xlink:type="locator" xlink:label="us-gaap_LeasesAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_LeasesAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_LeaseCostTableTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_LeaseCostTableTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LeasesAbstract" xlink:to="us-gaap_LeaseCostTableTextBlock" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_ScheduleOfFutureMinimumLeasePaymentsTableTextBlock" xlink:href="oprx-20211231.xsd#oprx_ScheduleOfFutureMinimumLeasePaymentsTableTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LeasesAbstract" xlink:to="oprx_ScheduleOfFutureMinimumLeasePaymentsTableTextBlock" order="1" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/MajorCustomersandVendorsTables">
    <loc xlink:type="locator" xlink:label="us-gaap_RisksAndUncertaintiesAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_RisksAndUncertaintiesAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ScheduleOfSegmentReportingInformationBySegmentTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ScheduleOfSegmentReportingInformationBySegmentTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_RisksAndUncertaintiesAbstract" xlink:to="us-gaap_ScheduleOfSegmentReportingInformationBySegmentTextBlock" order="0" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/IncomeTaxesTables">
    <loc xlink:type="locator" xlink:label="us-gaap_IncomeTaxDisclosureAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_IncomeTaxDisclosureAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ScheduleOfEffectiveIncomeTaxRateReconciliationTableTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ScheduleOfEffectiveIncomeTaxRateReconciliationTableTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeTaxDisclosureAbstract" xlink:to="us-gaap_ScheduleOfEffectiveIncomeTaxRateReconciliationTableTextBlock" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ScheduleOfDeferredTaxAssetsAndLiabilitiesTableTextBlock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ScheduleOfDeferredTaxAssetsAndLiabilitiesTableTextBlock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeTaxDisclosureAbstract" xlink:to="us-gaap_ScheduleOfDeferredTaxAssetsAndLiabilitiesTableTextBlock" order="1" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ScheduleoffinancialassetsandliabilitiesmeasuredonarecurringbasisTable">
    <loc xlink:type="locator" xlink:label="us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisValuationTechniquesLineItems" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisValuationTechniquesLineItems"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisValuationTechniquesTable" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisValuationTechniquesTable"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisValuationTechniquesLineItems" xlink:to="us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisValuationTechniquesTable" order="0" xbrldt:contextElement="segment" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FairValueByMeasurementFrequencyAxis" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FairValueByMeasurementFrequencyAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisValuationTechniquesTable" xlink:to="us-gaap_FairValueByMeasurementFrequencyAxis" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FairValueMeasurementFrequencyDomain" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FairValueMeasurementFrequencyDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_FairValueByMeasurementFrequencyAxis" xlink:to="us-gaap_FairValueMeasurementFrequencyDomain" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FairValueMeasurementFrequencyDomain_0" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FairValueMeasurementFrequencyDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_FairValueByMeasurementFrequencyAxis" xlink:to="us-gaap_FairValueMeasurementFrequencyDomain_0" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FairValueByFairValueHierarchyLevelAxis" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FairValueByFairValueHierarchyLevelAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisValuationTechniquesTable" xlink:to="us-gaap_FairValueByFairValueHierarchyLevelAxis" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FairValueMeasurementsFairValueHierarchyDomain" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FairValueMeasurementsFairValueHierarchyDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_FairValueByFairValueHierarchyLevelAxis" xlink:to="us-gaap_FairValueMeasurementsFairValueHierarchyDomain" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FairValueMeasurementsFairValueHierarchyDomain_0" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FairValueMeasurementsFairValueHierarchyDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_FairValueByFairValueHierarchyLevelAxis" xlink:to="us-gaap_FairValueMeasurementsFairValueHierarchyDomain_0" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FairValueInputsLevel1Member" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FairValueInputsLevel1Member"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FairValueMeasurementsFairValueHierarchyDomain" xlink:to="us-gaap_FairValueInputsLevel1Member" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FairValueInputsLevel2Member" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FairValueInputsLevel2Member"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FairValueMeasurementsFairValueHierarchyDomain" xlink:to="us-gaap_FairValueInputsLevel2Member" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FairValueInputsLevel3Member" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FairValueInputsLevel3Member"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FairValueMeasurementsFairValueHierarchyDomain" xlink:to="us-gaap_FairValueInputsLevel3Member" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FairValueMeasurementsRecurringMember" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FairValueMeasurementsRecurringMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FairValueMeasurementFrequencyDomain" xlink:to="us-gaap_FairValueMeasurementsRecurringMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_ContingentPurchasePricePayable" xlink:href="oprx-20211231.xsd#oprx_ContingentPurchasePricePayable"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisValuationTechniquesLineItems" xlink:to="oprx_ContingentPurchasePricePayable" order="1" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ScheduleofchangesinfairvalueoftheCompanysLevel3financialinstrumentsTable">
    <loc xlink:type="locator" xlink:label="oprx_ScheduleOfChangesInFairValueOfTheCompanySLevel3FinancialInstrumentsAbstract" xlink:href="oprx-20211231.xsd#oprx_ScheduleOfChangesInFairValueOfTheCompanySLevel3FinancialInstrumentsAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FairValueMeasurementWithUnobservableInputsReconciliationsRecurringBasisLiabilityValue" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FairValueMeasurementWithUnobservableInputsReconciliationsRecurringBasisLiabilityValue"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfChangesInFairValueOfTheCompanySLevel3FinancialInstrumentsAbstract" xlink:to="us-gaap_FairValueMeasurementWithUnobservableInputsReconciliationsRecurringBasisLiabilityValue" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_PaymentOfCareSpeakCommunicationContingentConsideration" xlink:href="oprx-20211231.xsd#oprx_PaymentOfCareSpeakCommunicationContingentConsideration"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfChangesInFairValueOfTheCompanySLevel3FinancialInstrumentsAbstract" xlink:to="oprx_PaymentOfCareSpeakCommunicationContingentConsideration" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_PaymentOfRMDYHealthIncContingentConsideration" xlink:href="oprx-20211231.xsd#oprx_PaymentOfRMDYHealthIncContingentConsideration"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfChangesInFairValueOfTheCompanySLevel3FinancialInstrumentsAbstract" xlink:to="oprx_PaymentOfRMDYHealthIncContingentConsideration" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_IncreaseInTheValueOfTheRMDYHealthIncContingentConsideration" xlink:href="oprx-20211231.xsd#oprx_IncreaseInTheValueOfTheRMDYHealthIncContingentConsideration"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfChangesInFairValueOfTheCompanySLevel3FinancialInstrumentsAbstract" xlink:to="oprx_IncreaseInTheValueOfTheRMDYHealthIncContingentConsideration" order="3" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ScheduleofrevenueisearnedfromlifesciencescompaniesTable">
    <loc xlink:type="locator" xlink:label="oprx_ScheduleOfRevenueIsEarnedFromLifeSciencesCompaniesAbstract" xlink:href="oprx-20211231.xsd#oprx_ScheduleOfRevenueIsEarnedFromLifeSciencesCompaniesAbstract"/>
    <loc xlink:type="locator" xlink:label="oprx_LifeScienceCompaniesRevenue" xlink:href="oprx-20211231.xsd#oprx_LifeScienceCompaniesRevenue"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfRevenueIsEarnedFromLifeSciencesCompaniesAbstract" xlink:to="oprx_LifeScienceCompaniesRevenue" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_OtherIncome" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OtherIncome"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfRevenueIsEarnedFromLifeSciencesCompaniesAbstract" xlink:to="us-gaap_OtherIncome" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_Revenues" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_Revenues"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfRevenueIsEarnedFromLifeSciencesCompaniesAbstract" xlink:to="us-gaap_Revenues" order="2" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ScheduleofexpecteddividendsTable">
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" order="0" xbrldt:contextElement="segment" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeAxis" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" xlink:to="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeAxis" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeAxis" xlink:to="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain_0" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeAxis" xlink:to="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain_0" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_MinimumMember" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_MinimumMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain" xlink:to="srt_MinimumMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_MaximumMember" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_MaximumMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain" xlink:to="srt_MaximumMember" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedDividendRate" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedDividendRate"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedDividendRate" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsRiskFreeInterestRate" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsRiskFreeInterestRate"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsRiskFreeInterestRate" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsTurnoverforfeitureRate" xlink:href="oprx-20211231.xsd#oprx_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsTurnoverforfeitureRate"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="oprx_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsTurnoverforfeitureRate" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedVolatilityRate" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedVolatilityRate"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedVolatilityRate" order="5" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_WeightedAverageGrantDateFairValueinDollarsPerShare" xlink:href="oprx-20211231.xsd#oprx_WeightedAverageGrantDateFairValueinDollarsPerShare"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="oprx_WeightedAverageGrantDateFairValueinDollarsPerShare" order="6" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ScheduleofweightedaveragesharesoutstandingandthebasicanddilutedearningspercommonshareTable">
    <loc xlink:type="locator" xlink:label="oprx_ScheduleOfWeightedAverageSharesOutstandingAndTheBasicAndDilutedEarningsPerCommonShareAbstract" xlink:href="oprx-20211231.xsd#oprx_ScheduleOfWeightedAverageSharesOutstandingAndTheBasicAndDilutedEarningsPerCommonShareAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_NetIncomeLossAvailableToCommonStockholdersBasic" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_NetIncomeLossAvailableToCommonStockholdersBasic"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfWeightedAverageSharesOutstandingAndTheBasicAndDilutedEarningsPerCommonShareAbstract" xlink:to="us-gaap_NetIncomeLossAvailableToCommonStockholdersBasic" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_WeightedAverageNumberOfSharesOutstandingBasic" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_WeightedAverageNumberOfSharesOutstandingBasic"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfWeightedAverageSharesOutstandingAndTheBasicAndDilutedEarningsPerCommonShareAbstract" xlink:to="us-gaap_WeightedAverageNumberOfSharesOutstandingBasic" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_EarningsPerShareBasic" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_EarningsPerShareBasic"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfWeightedAverageSharesOutstandingAndTheBasicAndDilutedEarningsPerCommonShareAbstract" xlink:to="us-gaap_EarningsPerShareBasic" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_NetIncomeLossAvailableToCommonStockholdersDiluted" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_NetIncomeLossAvailableToCommonStockholdersDiluted"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfWeightedAverageSharesOutstandingAndTheBasicAndDilutedEarningsPerCommonShareAbstract" xlink:to="us-gaap_NetIncomeLossAvailableToCommonStockholdersDiluted" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfWeightedAverageSharesOutstandingAndTheBasicAndDilutedEarningsPerCommonShareAbstract" xlink:to="us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_EarningsPerShareDiluted" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_EarningsPerShareDiluted"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfWeightedAverageSharesOutstandingAndTheBasicAndDilutedEarningsPerCommonShareAbstract" xlink:to="us-gaap_EarningsPerShareDiluted" order="5" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ScheduleofprepaidexpensesTable">
    <loc xlink:type="locator" xlink:label="oprx_ScheduleOfPrepaidExpensesAbstract" xlink:href="oprx-20211231.xsd#oprx_ScheduleOfPrepaidExpensesAbstract"/>
    <loc xlink:type="locator" xlink:label="oprx_PrepaidRevenueShareAndExclusivityPayments" xlink:href="oprx-20211231.xsd#oprx_PrepaidRevenueShareAndExclusivityPayments"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfPrepaidExpensesAbstract" xlink:to="oprx_PrepaidRevenueShareAndExclusivityPayments" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_PrepaidExpensesFees" xlink:href="oprx-20211231.xsd#oprx_PrepaidExpensesFees"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfPrepaidExpensesAbstract" xlink:to="oprx_PrepaidExpensesFees" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_PrepaidExpensesData" xlink:href="oprx-20211231.xsd#oprx_PrepaidExpensesData"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfPrepaidExpensesAbstract" xlink:to="oprx_PrepaidExpensesData" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_PrepaidInsurance" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PrepaidInsurance"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfPrepaidExpensesAbstract" xlink:to="us-gaap_PrepaidInsurance" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_OtherPrepaidExpenseCurrent" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OtherPrepaidExpenseCurrent"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfPrepaidExpensesAbstract" xlink:to="us-gaap_OtherPrepaidExpenseCurrent" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_PrepaidExpenseCurrent" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PrepaidExpenseCurrent"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfPrepaidExpensesAbstract" xlink:to="us-gaap_PrepaidExpenseCurrent" order="5" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ScheduleofpropertyandequipmentTable">
    <loc xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentLineItems" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PropertyPlantAndEquipmentLineItems"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ScheduleOfPropertyPlantAndEquipmentTable" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ScheduleOfPropertyPlantAndEquipmentTable"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_PropertyPlantAndEquipmentLineItems" xlink:to="us-gaap_ScheduleOfPropertyPlantAndEquipmentTable" order="0" xbrldt:contextElement="segment" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentByTypeAxis" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PropertyPlantAndEquipmentByTypeAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfPropertyPlantAndEquipmentTable" xlink:to="us-gaap_PropertyPlantAndEquipmentByTypeAxis" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentTypeDomain" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PropertyPlantAndEquipmentTypeDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_PropertyPlantAndEquipmentByTypeAxis" xlink:to="us-gaap_PropertyPlantAndEquipmentTypeDomain" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentTypeDomain_0" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PropertyPlantAndEquipmentTypeDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_PropertyPlantAndEquipmentByTypeAxis" xlink:to="us-gaap_PropertyPlantAndEquipmentTypeDomain_0" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ComputerEquipmentMember" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ComputerEquipmentMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PropertyPlantAndEquipmentTypeDomain" xlink:to="us-gaap_ComputerEquipmentMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FurnitureAndFixturesMember" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FurnitureAndFixturesMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PropertyPlantAndEquipmentTypeDomain" xlink:to="us-gaap_FurnitureAndFixturesMember" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentGross" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PropertyPlantAndEquipmentGross"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PropertyPlantAndEquipmentLineItems" xlink:to="us-gaap_PropertyPlantAndEquipmentGross" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_AccumulatedDepreciationDepletionAndAmortizationPropertyPlantAndEquipment" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_AccumulatedDepreciationDepletionAndAmortizationPropertyPlantAndEquipment"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PropertyPlantAndEquipmentLineItems" xlink:to="us-gaap_AccumulatedDepreciationDepletionAndAmortizationPropertyPlantAndEquipment" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentNet" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PropertyPlantAndEquipmentNet"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AccumulatedDepreciationDepletionAndAmortizationPropertyPlantAndEquipment" xlink:to="us-gaap_PropertyPlantAndEquipmentNet" order="0" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ScheduleofintangibleassetsincludedontheconsolidatedbalancesheetTable">
    <loc xlink:type="locator" xlink:label="oprx_IntangibleAssetsDetailsScheduleofintangibleassetsincludedontheconsolidatedbalancesheetLineItems" xlink:href="oprx-20211231.xsd#oprx_IntangibleAssetsDetailsScheduleofintangibleassetsincludedontheconsolidatedbalancesheetLineItems"/>
    <loc xlink:type="locator" xlink:label="oprx_IntangibleAssetsDetailsScheduleofintangibleassetsincludedontheconsolidatedbalancesheetTable" xlink:href="oprx-20211231.xsd#oprx_IntangibleAssetsDetailsScheduleofintangibleassetsincludedontheconsolidatedbalancesheetTable"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="oprx_IntangibleAssetsDetailsScheduleofintangibleassetsincludedontheconsolidatedbalancesheetLineItems" xlink:to="oprx_IntangibleAssetsDetailsScheduleofintangibleassetsincludedontheconsolidatedbalancesheetTable" order="0" xbrldt:contextElement="segment" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FiniteLivedIntangibleAssetsByMajorClassAxis" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FiniteLivedIntangibleAssetsByMajorClassAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="oprx_IntangibleAssetsDetailsScheduleofintangibleassetsincludedontheconsolidatedbalancesheetTable" xlink:to="us-gaap_FiniteLivedIntangibleAssetsByMajorClassAxis" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FiniteLivedIntangibleAssetsMajorClassNameDomain" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FiniteLivedIntangibleAssetsMajorClassNameDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_FiniteLivedIntangibleAssetsByMajorClassAxis" xlink:to="us-gaap_FiniteLivedIntangibleAssetsMajorClassNameDomain" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FiniteLivedIntangibleAssetsMajorClassNameDomain_0" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FiniteLivedIntangibleAssetsMajorClassNameDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_FiniteLivedIntangibleAssetsByMajorClassAxis" xlink:to="us-gaap_FiniteLivedIntangibleAssetsMajorClassNameDomain_0" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_EquitySecuritiesByIndustryAxis" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_EquitySecuritiesByIndustryAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="oprx_IntangibleAssetsDetailsScheduleofintangibleassetsincludedontheconsolidatedbalancesheetTable" xlink:to="us-gaap_EquitySecuritiesByIndustryAxis" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_EquitySecuritiesIndustryMember" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_EquitySecuritiesIndustryMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_EquitySecuritiesByIndustryAxis" xlink:to="us-gaap_EquitySecuritiesIndustryMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_EquitySecuritiesIndustryMember_0" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_EquitySecuritiesIndustryMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_EquitySecuritiesByIndustryAxis" xlink:to="us-gaap_EquitySecuritiesIndustryMember_0" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_PatentsMember" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PatentsMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FiniteLivedIntangibleAssetsMajorClassNameDomain" xlink:to="us-gaap_PatentsMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_TradeNamesMember" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_TradeNamesMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FiniteLivedIntangibleAssetsMajorClassNameDomain" xlink:to="us-gaap_TradeNamesMember" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_NoncompeteAgreementsMember" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_NoncompeteAgreementsMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FiniteLivedIntangibleAssetsMajorClassNameDomain" xlink:to="us-gaap_NoncompeteAgreementsMember" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_CustomerRelationshipsMember" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CustomerRelationshipsMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FiniteLivedIntangibleAssetsMajorClassNameDomain" xlink:to="us-gaap_CustomerRelationshipsMember" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_OtherIntangibleAssetsMember" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OtherIntangibleAssetsMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FiniteLivedIntangibleAssetsMajorClassNameDomain" xlink:to="us-gaap_OtherIntangibleAssetsMember" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_TechnologySectorMember" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_TechnologySectorMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EquitySecuritiesIndustryMember" xlink:to="us-gaap_TechnologySectorMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FiniteLivedIntangibleAssetsGross" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FiniteLivedIntangibleAssetsGross"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_IntangibleAssetsDetailsScheduleofintangibleassetsincludedontheconsolidatedbalancesheetLineItems" xlink:to="us-gaap_FiniteLivedIntangibleAssetsGross" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FiniteLivedIntangibleAssetsAccumulatedAmortization" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FiniteLivedIntangibleAssetsAccumulatedAmortization"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_IntangibleAssetsDetailsScheduleofintangibleassetsincludedontheconsolidatedbalancesheetLineItems" xlink:to="us-gaap_FiniteLivedIntangibleAssetsAccumulatedAmortization" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_IntangibleAssetsNetExcludingGoodwill" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_IntangibleAssetsNetExcludingGoodwill"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_IntangibleAssetsDetailsScheduleofintangibleassetsincludedontheconsolidatedbalancesheetLineItems" xlink:to="us-gaap_IntangibleAssetsNetExcludingGoodwill" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_AcquiredFiniteLivedIntangibleAssetsWeightedAverageUsefulLife" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_AcquiredFiniteLivedIntangibleAssetsWeightedAverageUsefulLife"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_IntangibleAssetsDetailsScheduleofintangibleassetsincludedontheconsolidatedbalancesheetLineItems" xlink:to="us-gaap_AcquiredFiniteLivedIntangibleAssetsWeightedAverageUsefulLife" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_OtherIntangibleAssetsAbstract0" xlink:href="oprx-20211231.xsd#oprx_OtherIntangibleAssetsAbstract0"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_IntangibleAssetsDetailsScheduleofintangibleassetsincludedontheconsolidatedbalancesheetLineItems" xlink:to="oprx_OtherIntangibleAssetsAbstract0" order="5" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_OtherIntangibleAssetsAbstract" xlink:href="oprx-20211231.xsd#oprx_OtherIntangibleAssetsAbstract"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_IntangibleAssetsDetailsScheduleofintangibleassetsincludedontheconsolidatedbalancesheetLineItems" xlink:to="oprx_OtherIntangibleAssetsAbstract" order="6" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ScheduleofintangiblesestimatedusefullivesTable">
    <loc xlink:type="locator" xlink:label="us-gaap_FiniteLivedIntangibleAssetsLineItems" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FiniteLivedIntangibleAssetsLineItems"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ScheduleOfFiniteLivedIntangibleAssetsTable" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ScheduleOfFiniteLivedIntangibleAssetsTable"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_FiniteLivedIntangibleAssetsLineItems" xlink:to="us-gaap_ScheduleOfFiniteLivedIntangibleAssetsTable" order="0" xbrldt:contextElement="segment" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FiniteLivedIntangibleAssetsByMajorClassAxis" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FiniteLivedIntangibleAssetsByMajorClassAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfFiniteLivedIntangibleAssetsTable" xlink:to="us-gaap_FiniteLivedIntangibleAssetsByMajorClassAxis" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FiniteLivedIntangibleAssetsMajorClassNameDomain" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FiniteLivedIntangibleAssetsMajorClassNameDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_FiniteLivedIntangibleAssetsByMajorClassAxis" xlink:to="us-gaap_FiniteLivedIntangibleAssetsMajorClassNameDomain" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FiniteLivedIntangibleAssetsMajorClassNameDomain_0" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FiniteLivedIntangibleAssetsMajorClassNameDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_FiniteLivedIntangibleAssetsByMajorClassAxis" xlink:to="us-gaap_FiniteLivedIntangibleAssetsMajorClassNameDomain_0" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_EquitySecuritiesByIndustryAxis" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_EquitySecuritiesByIndustryAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfFiniteLivedIntangibleAssetsTable" xlink:to="us-gaap_EquitySecuritiesByIndustryAxis" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_EquitySecuritiesIndustryMember" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_EquitySecuritiesIndustryMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_EquitySecuritiesByIndustryAxis" xlink:to="us-gaap_EquitySecuritiesIndustryMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_EquitySecuritiesIndustryMember_0" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_EquitySecuritiesIndustryMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_EquitySecuritiesByIndustryAxis" xlink:to="us-gaap_EquitySecuritiesIndustryMember_0" order="1" xbrldt:closed="true"/>
<!-- [WMV5][XcpuxYn59dz7vgYynUDuwG7r97K2jUTysl7vcz0lJt/tSeJz73kx1cLt0ZFF2SK/vxBCY0vdSrY3zgwHHioNV2cohiuDFf+hwvm7ENIq/CcPNpwjKdmt1EcmBHkr6foMwUdCMU0KgYP9Y8fM2DbKpO4BSJ3rFrDERdg+cDqQIRue7iikOvAkl2Z1FWC6j1R0ioOVOgBU/VSP9f4iNqHVpPVoOaS5gUB7zFxgAnuCp3CK9/vIaMKAZrjGHfPlHSu0ZMpss3DiQ9O/ZZoy9pLJyA==] CSR-->
    <loc xlink:type="locator" xlink:label="srt_RangeAxis" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_RangeAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfFiniteLivedIntangibleAssetsTable" xlink:to="srt_RangeAxis" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_RangeMember" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_RangeMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_RangeAxis" xlink:to="srt_RangeMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_RangeMember_0" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_RangeMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="srt_RangeAxis" xlink:to="srt_RangeMember_0" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_PatentsMember" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PatentsMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FiniteLivedIntangibleAssetsMajorClassNameDomain" xlink:to="us-gaap_PatentsMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_TradeNamesMember" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_TradeNamesMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FiniteLivedIntangibleAssetsMajorClassNameDomain" xlink:to="us-gaap_TradeNamesMember" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_NoncompeteAgreementsMember" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_NoncompeteAgreementsMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FiniteLivedIntangibleAssetsMajorClassNameDomain" xlink:to="us-gaap_NoncompeteAgreementsMember" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_CustomerRelationshipsMember" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CustomerRelationshipsMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FiniteLivedIntangibleAssetsMajorClassNameDomain" xlink:to="us-gaap_CustomerRelationshipsMember" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_MinimumMember" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_MinimumMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MinimumMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_MaximumMember" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_MaximumMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MaximumMember" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_TechnologySectorMember" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_TechnologySectorMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EquitySecuritiesIndustryMember" xlink:to="us-gaap_TechnologySectorMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FiniteLivedIntangibleAssetUsefulLife" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FiniteLivedIntangibleAssetUsefulLife"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FiniteLivedIntangibleAssetsLineItems" xlink:to="us-gaap_FiniteLivedIntangibleAssetUsefulLife" order="1" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ScheduleoffutureamortizationexpensesofintangiblesassetsTable">
    <loc xlink:type="locator" xlink:label="oprx_ScheduleOfFutureAmortizationExpensesOfIntangiblesAssetsAbstract" xlink:href="oprx-20211231.xsd#oprx_ScheduleOfFutureAmortizationExpensesOfIntangiblesAssetsAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseNextTwelveMonths" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseNextTwelveMonths"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfFutureAmortizationExpensesOfIntangiblesAssetsAbstract" xlink:to="us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseNextTwelveMonths" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearTwo" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearTwo"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfFutureAmortizationExpensesOfIntangiblesAssetsAbstract" xlink:to="us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearTwo" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearThree" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearThree"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfFutureAmortizationExpensesOfIntangiblesAssetsAbstract" xlink:to="us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearThree" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFour" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFour"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfFutureAmortizationExpensesOfIntangiblesAssetsAbstract" xlink:to="us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFour" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFive" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFive"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfFutureAmortizationExpensesOfIntangiblesAssetsAbstract" xlink:to="us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFive" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseAfterYearFive" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseAfterYearFive"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFive" xlink:to="us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseAfterYearFive" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FiniteLivedIntangibleAssetsNet" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FiniteLivedIntangibleAssetsNet"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfFutureAmortizationExpensesOfIntangiblesAssetsAbstract" xlink:to="us-gaap_FiniteLivedIntangibleAssetsNet" order="5" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ScheduleofdeferredrevenueTable">
    <loc xlink:type="locator" xlink:label="oprx_ScheduleOfDeferredRevenueAbstract" xlink:href="oprx-20211231.xsd#oprx_ScheduleOfDeferredRevenueAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_DeferredRevenue" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DeferredRevenue"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfDeferredRevenueAbstract" xlink:to="us-gaap_DeferredRevenue" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_DeferredRevenueRevenueRecognized1" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DeferredRevenueRevenueRecognized1"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfDeferredRevenueAbstract" xlink:to="us-gaap_DeferredRevenueRevenueRecognized1" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_UnrealizedGainLossOnInvestments" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_UnrealizedGainLossOnInvestments"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfDeferredRevenueAbstract" xlink:to="us-gaap_UnrealizedGainLossOnInvestments" order="2" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ScheduleoffairvalueofcontingentpurchasepricepayableTable">
    <loc xlink:type="locator" xlink:label="oprx_ContingentPurchasePriceDetailsScheduleoffairvalueofcontingentpurchasepricepayableLineItems" xlink:href="oprx-20211231.xsd#oprx_ContingentPurchasePriceDetailsScheduleoffairvalueofcontingentpurchasepricepayableLineItems"/>
    <loc xlink:type="locator" xlink:label="oprx_ContingentPurchasePriceDetailsScheduleoffairvalueofcontingentpurchasepricepayableTable" xlink:href="oprx-20211231.xsd#oprx_ContingentPurchasePriceDetailsScheduleoffairvalueofcontingentpurchasepricepayableTable"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="oprx_ContingentPurchasePriceDetailsScheduleoffairvalueofcontingentpurchasepricepayableLineItems" xlink:to="oprx_ContingentPurchasePriceDetailsScheduleoffairvalueofcontingentpurchasepricepayableTable" order="0" xbrldt:contextElement="segment" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_RelatedPartyTransactionAxis" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_RelatedPartyTransactionAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="oprx_ContingentPurchasePriceDetailsScheduleoffairvalueofcontingentpurchasepricepayableTable" xlink:to="us-gaap_RelatedPartyTransactionAxis" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_RelatedPartyTransactionDomain" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_RelatedPartyTransactionDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_RelatedPartyTransactionAxis" xlink:to="us-gaap_RelatedPartyTransactionDomain" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_RelatedPartyTransactionDomain_0" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_RelatedPartyTransactionDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_RelatedPartyTransactionAxis" xlink:to="us-gaap_RelatedPartyTransactionDomain_0" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ExtinguishmentOfDebtAxis" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ExtinguishmentOfDebtAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="oprx_ContingentPurchasePriceDetailsScheduleoffairvalueofcontingentpurchasepricepayableTable" xlink:to="us-gaap_ExtinguishmentOfDebtAxis" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ExtinguishmentOfDebtTypeDomain" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ExtinguishmentOfDebtTypeDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_ExtinguishmentOfDebtAxis" xlink:to="us-gaap_ExtinguishmentOfDebtTypeDomain" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ExtinguishmentOfDebtTypeDomain_0" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ExtinguishmentOfDebtTypeDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_ExtinguishmentOfDebtAxis" xlink:to="us-gaap_ExtinguishmentOfDebtTypeDomain_0" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_CurrentMember" xlink:href="oprx-20211231.xsd#oprx_CurrentMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ExtinguishmentOfDebtTypeDomain" xlink:to="oprx_CurrentMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_LongTermMember" xlink:href="oprx-20211231.xsd#oprx_LongTermMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ExtinguishmentOfDebtTypeDomain" xlink:to="oprx_LongTermMember" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_CareSpeakCommunicationsIncMember" xlink:href="oprx-20211231.xsd#oprx_CareSpeakCommunicationsIncMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_RelatedPartyTransactionDomain" xlink:to="oprx_CareSpeakCommunicationsIncMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_RMDYHealthMember" xlink:href="oprx-20211231.xsd#oprx_RMDYHealthMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_RelatedPartyTransactionDomain" xlink:to="oprx_RMDYHealthMember" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_FairValueOfContingentPurchasePricePayable" xlink:href="oprx-20211231.xsd#oprx_FairValueOfContingentPurchasePricePayable"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ContingentPurchasePriceDetailsScheduleoffairvalueofcontingentpurchasepricepayableLineItems" xlink:to="oprx_FairValueOfContingentPurchasePricePayable" order="1" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ScheduleofoptionactivityTable">
    <loc xlink:type="locator" xlink:label="oprx_ScheduleOfOptionActivityAbstract" xlink:href="oprx-20211231.xsd#oprx_ScheduleOfOptionActivityAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfOptionActivityAbstract" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePrice" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePrice"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfOptionActivityAbstract" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePrice" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriod" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriod"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfOptionActivityAbstract" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriod" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageExercisePrice" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageExercisePrice"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfOptionActivityAbstract" xlink:to="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageExercisePrice" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageExercisePrice" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsExercisableInPeriodWeightedAverageExercisePrice" xlink:href="oprx-20211231.xsd#oprx_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsExercisableInPeriodWeightedAverageExercisePrice"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageExercisePrice" xlink:to="oprx_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsExercisableInPeriodWeightedAverageExercisePrice" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableWeightedAverageRemainingContractualTerm1" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableWeightedAverageRemainingContractualTerm1"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageExercisePrice" xlink:to="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableWeightedAverageRemainingContractualTerm1" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableIntrinsicValue1" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableIntrinsicValue1"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageExercisePrice" xlink:to="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableIntrinsicValue1" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNonOptionEquityInstrumentsExercised" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNonOptionEquityInstrumentsExercised"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfOptionActivityAbstract" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNonOptionEquityInstrumentsExercised" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageExercisePrice" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageExercisePrice"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfOptionActivityAbstract" xlink:to="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageExercisePrice" order="5" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsForfeituresAndExpirationsInPeriod" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsForfeituresAndExpirationsInPeriod"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfOptionActivityAbstract" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsForfeituresAndExpirationsInPeriod" order="6" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsForfeituresAndExpirationsInPeriodWeightedAverageExercisePrice" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsForfeituresAndExpirationsInPeriodWeightedAverageExercisePrice"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfOptionActivityAbstract" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsForfeituresAndExpirationsInPeriodWeightedAverageExercisePrice" order="7" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_SharebasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeOutstandingOptionsWeightedAverageRemainingContractualTerm2" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SharebasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeOutstandingOptionsWeightedAverageRemainingContractualTerm2"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfOptionActivityAbstract" xlink:to="us-gaap_SharebasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeOutstandingOptionsWeightedAverageRemainingContractualTerm2" order="8" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingIntrinsicValue" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingIntrinsicValue"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfOptionActivityAbstract" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingIntrinsicValue" order="9" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ScheduleoftotalandvestedoptionsoutstandingTable">
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeLineItems" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeLineItems"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ScheduleOfShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeTable" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ScheduleOfShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeTable"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeLineItems" xlink:to="us-gaap_ScheduleOfShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeTable" order="0" xbrldt:contextElement="segment" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_DerivativeInstrumentRiskAxis" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DerivativeInstrumentRiskAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeTable" xlink:to="us-gaap_DerivativeInstrumentRiskAxis" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_DerivativeContractTypeDomain" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DerivativeContractTypeDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_DerivativeInstrumentRiskAxis" xlink:to="us-gaap_DerivativeContractTypeDomain" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_DerivativeContractTypeDomain_0" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DerivativeContractTypeDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_DerivativeInstrumentRiskAxis" xlink:to="us-gaap_DerivativeContractTypeDomain_0" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeAxis" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeTable" xlink:to="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeAxis" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeAxis" xlink:to="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain_0" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeAxis" xlink:to="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain_0" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_RangeAxis" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_RangeAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeTable" xlink:to="srt_RangeAxis" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_RangeMember" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_RangeMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_RangeAxis" xlink:to="srt_RangeMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_RangeMember_0" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_RangeMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="srt_RangeAxis" xlink:to="srt_RangeMember_0" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_ExercisePriceRangeOneMember" xlink:href="oprx-20211231.xsd#oprx_ExercisePriceRangeOneMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain" xlink:to="oprx_ExercisePriceRangeOneMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_ExercisePriceRangeTwoMember" xlink:href="oprx-20211231.xsd#oprx_ExercisePriceRangeTwoMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain" xlink:to="oprx_ExercisePriceRangeTwoMember" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_ExercisePriceRangeThreeMember" xlink:href="oprx-20211231.xsd#oprx_ExercisePriceRangeThreeMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain" xlink:to="oprx_ExercisePriceRangeThreeMember" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_ExercisePriceRangeFourMember" xlink:href="oprx-20211231.xsd#oprx_ExercisePriceRangeFourMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain" xlink:to="oprx_ExercisePriceRangeFourMember" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_ExercisePriceRangeFiveMember" xlink:href="oprx-20211231.xsd#oprx_ExercisePriceRangeFiveMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain" xlink:to="oprx_ExercisePriceRangeFiveMember" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_ExercisePriceRangeMember" xlink:href="oprx-20211231.xsd#oprx_ExercisePriceRangeMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain" xlink:to="oprx_ExercisePriceRangeMember" order="5" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_MinimumMember" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_MinimumMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MinimumMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_MaximumMember" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_MaximumMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MaximumMember" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_TotalOptionOutstandingMember" xlink:href="oprx-20211231.xsd#oprx_TotalOptionOutstandingMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DerivativeContractTypeDomain" xlink:to="oprx_TotalOptionOutstandingMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_VestedOptionsOutstandingMember" xlink:href="oprx-20211231.xsd#oprx_VestedOptionsOutstandingMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DerivativeContractTypeDomain" xlink:to="oprx_VestedOptionsOutstandingMember" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeNumberOfOutstandingOptions" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeNumberOfOutstandingOptions"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeLineItems" xlink:to="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeNumberOfOutstandingOptions" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableWeightedAverageRemainingContractualTerm1" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableWeightedAverageRemainingContractualTerm1"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeLineItems" xlink:to="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableWeightedAverageRemainingContractualTerm1" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_SharebasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeExercisableOptionsWeightedAverageExercisePrice1" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SharebasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeExercisableOptionsWeightedAverageExercisePrice1"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeLineItems" xlink:to="us-gaap_SharebasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeExercisableOptionsWeightedAverageExercisePrice1" order="4" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ScheduleofnonvestedsharesTable">
    <loc xlink:type="locator" xlink:label="oprx_ScheduleOfNonvestedSharesAbstract" xlink:href="oprx-20211231.xsd#oprx_ScheduleOfNonvestedSharesAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsNonvestedNumberOfShares" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsNonvestedNumberOfShares"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfNonvestedSharesAbstract" xlink:to="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsNonvestedNumberOfShares" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsNonvestedWeightedAverageGrantDateFairValue" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsNonvestedWeightedAverageGrantDateFairValue"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfNonvestedSharesAbstract" xlink:to="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsNonvestedWeightedAverageGrantDateFairValue" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodGross" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodGross"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfNonvestedSharesAbstract" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodGross" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfNonvestedSharesAbstract" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsVestedNumberOfShares" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsVestedNumberOfShares"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfNonvestedSharesAbstract" xlink:to="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsVestedNumberOfShares" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsVestedWeightedAverageGrantDateFairValue" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsVestedWeightedAverageGrantDateFairValue"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfNonvestedSharesAbstract" xlink:to="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsVestedWeightedAverageGrantDateFairValue" order="5" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsNonvestedOptionsForfeitedNumberOfShares" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsNonvestedOptionsForfeitedNumberOfShares"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfNonvestedSharesAbstract" xlink:to="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsNonvestedOptionsForfeitedNumberOfShares" order="6" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsNonvestedOptionsForfeitedWeightedAverageGrantDateFairValue" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsNonvestedOptionsForfeitedWeightedAverageGrantDateFairValue"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfNonvestedSharesAbstract" xlink:to="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsNonvestedOptionsForfeitedWeightedAverageGrantDateFairValue" order="7" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ScheduleofrestrictedstockawardsTable">
    <loc xlink:type="locator" xlink:label="oprx_ScheduleOfRestrictedStockAwardsAbstract" xlink:href="oprx-20211231.xsd#oprx_ScheduleOfRestrictedStockAwardsAbstract"/>
    <loc xlink:type="locator" xlink:label="oprx_SharebasedCompensationArrangementBySharebasedPaymentRestrictedStockAwardsSharesOutstandingBeginning" xlink:href="oprx-20211231.xsd#oprx_SharebasedCompensationArrangementBySharebasedPaymentRestrictedStockAwardsSharesOutstandingBeginning"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfRestrictedStockAwardsAbstract" xlink:to="oprx_SharebasedCompensationArrangementBySharebasedPaymentRestrictedStockAwardsSharesOutstandingBeginning" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_GrantDateFairValueOutstandingBeginning" xlink:href="oprx-20211231.xsd#oprx_GrantDateFairValueOutstandingBeginning"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfRestrictedStockAwardsAbstract" xlink:to="oprx_GrantDateFairValueOutstandingBeginning" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_SharebasedCompensationArrangementBySharebasedPaymentRestrictedStockAwardsSharesGranted" xlink:href="oprx-20211231.xsd#oprx_SharebasedCompensationArrangementBySharebasedPaymentRestrictedStockAwardsSharesGranted"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfRestrictedStockAwardsAbstract" xlink:to="oprx_SharebasedCompensationArrangementBySharebasedPaymentRestrictedStockAwardsSharesGranted" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_SharebasedCompensationArrangementBySharebasedPaymentRestrictedStockAwardsWeightedAverageGrantDateFairValueGranted" xlink:href="oprx-20211231.xsd#oprx_SharebasedCompensationArrangementBySharebasedPaymentRestrictedStockAwardsWeightedAverageGrantDateFairValueGranted"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfRestrictedStockAwardsAbstract" xlink:to="oprx_SharebasedCompensationArrangementBySharebasedPaymentRestrictedStockAwardsWeightedAverageGrantDateFairValueGranted" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsForfeituresInPeriod" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsForfeituresInPeriod"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfRestrictedStockAwardsAbstract" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsForfeituresInPeriod" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_GrantDateFairValueForfeited" xlink:href="oprx-20211231.xsd#oprx_GrantDateFairValueForfeited"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfRestrictedStockAwardsAbstract" xlink:to="oprx_GrantDateFairValueForfeited" order="5" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_SharebasedCompensationArrangementBySharebasedPaymentRestrictedStockAwardsSharesVestedAndIssued" xlink:href="oprx-20211231.xsd#oprx_SharebasedCompensationArrangementBySharebasedPaymentRestrictedStockAwardsSharesVestedAndIssued"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfRestrictedStockAwardsAbstract" xlink:to="oprx_SharebasedCompensationArrangementBySharebasedPaymentRestrictedStockAwardsSharesVestedAndIssued" order="6" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_SharebasedCompensationArrangementBySharebasedPaymentRestrictedStockAwardsWeightedAverageGrantDateFairValueVestedAndIssued" xlink:href="oprx-20211231.xsd#oprx_SharebasedCompensationArrangementBySharebasedPaymentRestrictedStockAwardsWeightedAverageGrantDateFairValueVestedAndIssued"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfRestrictedStockAwardsAbstract" xlink:to="oprx_SharebasedCompensationArrangementBySharebasedPaymentRestrictedStockAwardsWeightedAverageGrantDateFairValueVestedAndIssued" order="7" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_SharebasedCompensationArrangementBySharebasedPaymentRestrictedStockAwardsWeightedAverageGrantDateFairValueOutstandingEnding" xlink:href="oprx-20211231.xsd#oprx_SharebasedCompensationArrangementBySharebasedPaymentRestrictedStockAwardsWeightedAverageGrantDateFairValueOutstandingEnding"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfRestrictedStockAwardsAbstract" xlink:to="oprx_SharebasedCompensationArrangementBySharebasedPaymentRestrictedStockAwardsWeightedAverageGrantDateFairValueOutstandingEnding" order="8" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_SharebasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeExercisableOptionsWeightedAverageRemainingContractualTerm2" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SharebasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeExercisableOptionsWeightedAverageRemainingContractualTerm2"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfRestrictedStockAwardsAbstract" xlink:to="us-gaap_SharebasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeExercisableOptionsWeightedAverageRemainingContractualTerm2" order="9" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ScheduleofleasecostTable">
    <loc xlink:type="locator" xlink:label="oprx_ScheduleOfLeaseCostAbstract" xlink:href="oprx-20211231.xsd#oprx_ScheduleOfLeaseCostAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_OperatingLeaseCost" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OperatingLeaseCost"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfLeaseCostAbstract" xlink:to="us-gaap_OperatingLeaseCost" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShortTermLeaseCost" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShortTermLeaseCost"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfLeaseCostAbstract" xlink:to="us-gaap_ShortTermLeaseCost" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_LeaseCost" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_LeaseCost"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfLeaseCostAbstract" xlink:to="us-gaap_LeaseCost" order="2" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ScheduleoffutureminimumleasepaymentsTable">
    <loc xlink:type="locator" xlink:label="oprx_ScheduleOfFutureMinimumLeasePaymentsAbstract" xlink:href="oprx-20211231.xsd#oprx_ScheduleOfFutureMinimumLeasePaymentsAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueNextTwelveMonths" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueNextTwelveMonths"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfFutureMinimumLeasePaymentsAbstract" xlink:to="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueNextTwelveMonths" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearTwo" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearTwo"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfFutureMinimumLeasePaymentsAbstract" xlink:to="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearTwo" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearThree" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearThree"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfFutureMinimumLeasePaymentsAbstract" xlink:to="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearThree" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFour" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFour"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfFutureMinimumLeasePaymentsAbstract" xlink:to="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFour" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFour" xlink:to="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_LesseeOperatingLeaseLiabilityUndiscountedExcessAmount" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_LesseeOperatingLeaseLiabilityUndiscountedExcessAmount"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFour" xlink:to="us-gaap_LesseeOperatingLeaseLiabilityUndiscountedExcessAmount" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_TotalLeaseLiabilities" xlink:href="oprx-20211231.xsd#oprx_TotalLeaseLiabilities"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFour" xlink:to="oprx_TotalLeaseLiabilities" order="2" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ScheduleofcustomersaccountedpercentageofrevenueTable">
    <loc xlink:type="locator" xlink:label="us-gaap_SegmentReportingInformationLineItems" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SegmentReportingInformationLineItems"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ScheduleOfSegmentReportingInformationBySegmentTable" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ScheduleOfSegmentReportingInformationBySegmentTable"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_SegmentReportingInformationLineItems" xlink:to="us-gaap_ScheduleOfSegmentReportingInformationBySegmentTable" order="0" xbrldt:contextElement="segment" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_MajorCustomersAxis" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_MajorCustomersAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfSegmentReportingInformationBySegmentTable" xlink:to="srt_MajorCustomersAxis" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_NameOfMajorCustomerDomain" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_NameOfMajorCustomerDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_MajorCustomersAxis" xlink:to="srt_NameOfMajorCustomerDomain" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_NameOfMajorCustomerDomain_0" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_NameOfMajorCustomerDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="srt_MajorCustomersAxis" xlink:to="srt_NameOfMajorCustomerDomain_0" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_CustomerAMember" xlink:href="oprx-20211231.xsd#oprx_CustomerAMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_NameOfMajorCustomerDomain" xlink:to="oprx_CustomerAMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_CustomerBMember" xlink:href="oprx-20211231.xsd#oprx_CustomerBMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_NameOfMajorCustomerDomain" xlink:to="oprx_CustomerBMember" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_CustomerCMember" xlink:href="oprx-20211231.xsd#oprx_CustomerCMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_NameOfMajorCustomerDomain" xlink:to="oprx_CustomerCMember" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_PartnerAMember" xlink:href="oprx-20211231.xsd#oprx_PartnerAMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_NameOfMajorCustomerDomain" xlink:to="oprx_PartnerAMember" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_PartnerBMember" xlink:href="oprx-20211231.xsd#oprx_PartnerBMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_NameOfMajorCustomerDomain" xlink:to="oprx_PartnerBMember" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_Revenues" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_Revenues"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SegmentReportingInformationLineItems" xlink:to="us-gaap_Revenues" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_ConcentrationRiskPercentage" xlink:href="oprx-20211231.xsd#oprx_ConcentrationRiskPercentage"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SegmentReportingInformationLineItems" xlink:to="oprx_ConcentrationRiskPercentage" order="2" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ScheduleoffederalincometaxbenefitTable">
    <loc xlink:type="locator" xlink:label="oprx_ScheduleOfFederalIncomeTaxBenefitAbstract" xlink:href="oprx-20211231.xsd#oprx_ScheduleOfFederalIncomeTaxBenefitAbstract"/>
    <loc xlink:type="locator" xlink:label="oprx_FederalIncomeTaxBenefitExpenseAttributableToAbstract" xlink:href="oprx-20211231.xsd#oprx_FederalIncomeTaxBenefitExpenseAttributableToAbstract"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfFederalIncomeTaxBenefitAbstract" xlink:to="oprx_FederalIncomeTaxBenefitExpenseAttributableToAbstract" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_CurrentFederalTaxExpenseBenefit" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CurrentFederalTaxExpenseBenefit"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_FederalIncomeTaxBenefitExpenseAttributableToAbstract" xlink:to="us-gaap_CurrentFederalTaxExpenseBenefit" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_FederalIncomeTaxStateTaxEffectNetOfFederalBenefit" xlink:href="oprx-20211231.xsd#oprx_FederalIncomeTaxStateTaxEffectNetOfFederalBenefit"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_FederalIncomeTaxBenefitExpenseAttributableToAbstract" xlink:to="oprx_FederalIncomeTaxStateTaxEffectNetOfFederalBenefit" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_FederalIncomeTaxStateRateChange" xlink:href="oprx-20211231.xsd#oprx_FederalIncomeTaxStateRateChange"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_FederalIncomeTaxBenefitExpenseAttributableToAbstract" xlink:to="oprx_FederalIncomeTaxStateRateChange" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_FederalIncomeTaxChangeInFairValueOfContingentConsideration" xlink:href="oprx-20211231.xsd#oprx_FederalIncomeTaxChangeInFairValueOfContingentConsideration"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_FederalIncomeTaxBenefitExpenseAttributableToAbstract" xlink:to="oprx_FederalIncomeTaxChangeInFairValueOfContingentConsideration" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_FederalIncomeTaxOptionExerciseBenefitsNetOfSection162MLimitations" xlink:href="oprx-20211231.xsd#oprx_FederalIncomeTaxOptionExerciseBenefitsNetOfSection162MLimitations"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_FederalIncomeTaxBenefitExpenseAttributableToAbstract" xlink:to="oprx_FederalIncomeTaxOptionExerciseBenefitsNetOfSection162MLimitations" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_FederalIncomeTaxOtherPermanentItems" xlink:href="oprx-20211231.xsd#oprx_FederalIncomeTaxOtherPermanentItems"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_FederalIncomeTaxBenefitExpenseAttributableToAbstract" xlink:to="oprx_FederalIncomeTaxOtherPermanentItems" order="5" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_FederalIncomeTaxOtherAdjustments" xlink:href="oprx-20211231.xsd#oprx_FederalIncomeTaxOtherAdjustments"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_FederalIncomeTaxBenefitExpenseAttributableToAbstract" xlink:to="oprx_FederalIncomeTaxOtherAdjustments" order="6" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_FederalIncomeTaxNetOperatingLossExpiring" xlink:href="oprx-20211231.xsd#oprx_FederalIncomeTaxNetOperatingLossExpiring"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_FederalIncomeTaxBenefitExpenseAttributableToAbstract" xlink:to="oprx_FederalIncomeTaxNetOperatingLossExpiring" order="7" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_FederalIncomeTaxExpensesBenefitValueAllowance" xlink:href="oprx-20211231.xsd#oprx_FederalIncomeTaxExpensesBenefitValueAllowance"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_FederalIncomeTaxBenefitExpenseAttributableToAbstract" xlink:to="oprx_FederalIncomeTaxExpensesBenefitValueAllowance" order="8" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FederalIncomeTaxExpenseBenefitContinuingOperations" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FederalIncomeTaxExpenseBenefitContinuingOperations"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_FederalIncomeTaxBenefitExpenseAttributableToAbstract" xlink:to="us-gaap_FederalIncomeTaxExpenseBenefitContinuingOperations" order="9" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_CurrentForeignTaxExpenseBenefit" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CurrentForeignTaxExpenseBenefit"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_FederalIncomeTaxBenefitExpenseAttributableToAbstract" xlink:to="us-gaap_CurrentForeignTaxExpenseBenefit" order="10" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_DeferredFederalIncomeTaxExpenseBenefit" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DeferredFederalIncomeTaxExpenseBenefit"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_FederalIncomeTaxBenefitExpenseAttributableToAbstract" xlink:to="us-gaap_DeferredFederalIncomeTaxExpenseBenefit" order="11" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_TaxAdjustmentsSettlementsAndUnusualProvisions" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_TaxAdjustmentsSettlementsAndUnusualProvisions"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_FederalIncomeTaxBenefitExpenseAttributableToAbstract" xlink:to="us-gaap_TaxAdjustmentsSettlementsAndUnusualProvisions" order="12" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_IncomeTaxExpenseBenefit" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_IncomeTaxExpenseBenefit"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_FederalIncomeTaxBenefitExpenseAttributableToAbstract" xlink:to="us-gaap_IncomeTaxExpenseBenefit" order="13" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ScheduleofdeferredtaxassetsTable">
    <loc xlink:type="locator" xlink:label="oprx_ScheduleOfDeferredTaxAssetsAbstract" xlink:href="oprx-20211231.xsd#oprx_ScheduleOfDeferredTaxAssetsAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_DeferredTaxAssetsOperatingLossCarryforwards" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DeferredTaxAssetsOperatingLossCarryforwards"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfDeferredTaxAssetsAbstract" xlink:to="us-gaap_DeferredTaxAssetsOperatingLossCarryforwards" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_DeferredTaxAssetsTaxDeferredExpenseCompensationAndBenefitsShareBasedCompensationCost" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DeferredTaxAssetsTaxDeferredExpenseCompensationAndBenefitsShareBasedCompensationCost"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfDeferredTaxAssetsAbstract" xlink:to="us-gaap_DeferredTaxAssetsTaxDeferredExpenseCompensationAndBenefitsShareBasedCompensationCost" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_DeferredTaxAssetsOperatingLeaseLiability" xlink:href="oprx-20211231.xsd#oprx_DeferredTaxAssetsOperatingLeaseLiability"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfDeferredTaxAssetsAbstract" xlink:to="oprx_DeferredTaxAssetsOperatingLeaseLiability" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_DeferredTaxAssetsGoodwillAndIntangibleAssets" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DeferredTaxAssetsGoodwillAndIntangibleAssets"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfDeferredTaxAssetsAbstract" xlink:to="us-gaap_DeferredTaxAssetsGoodwillAndIntangibleAssets" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_DeferredTaxAssetsOther" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DeferredTaxAssetsOther"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfDeferredTaxAssetsAbstract" xlink:to="us-gaap_DeferredTaxAssetsOther" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_DeferredTaxAssetsGross" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DeferredTaxAssetsGross"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfDeferredTaxAssetsAbstract" xlink:to="us-gaap_DeferredTaxAssetsGross" order="5" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_DeferredTaxLiabilitiesGoodwillAndIntangibleAssetsIntangibleAssets" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DeferredTaxLiabilitiesGoodwillAndIntangibleAssetsIntangibleAssets"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfDeferredTaxAssetsAbstract" xlink:to="us-gaap_DeferredTaxLiabilitiesGoodwillAndIntangibleAssetsIntangibleAssets" order="6" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_DeferredTaxLiabilitiesOperatingLeaseRightOfUseAssets" xlink:href="oprx-20211231.xsd#oprx_DeferredTaxLiabilitiesOperatingLeaseRightOfUseAssets"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfDeferredTaxAssetsAbstract" xlink:to="oprx_DeferredTaxLiabilitiesOperatingLeaseRightOfUseAssets" order="7" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_DeferredTaxLiabilitiesOther" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DeferredTaxLiabilitiesOther"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfDeferredTaxAssetsAbstract" xlink:to="us-gaap_DeferredTaxLiabilitiesOther" order="8" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_DeferredTaxLiabilities" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DeferredTaxLiabilities"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfDeferredTaxAssetsAbstract" xlink:to="us-gaap_DeferredTaxLiabilities" order="9" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_DeferredTaxAssetsNet" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DeferredTaxAssetsNet"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfDeferredTaxAssetsAbstract" xlink:to="us-gaap_DeferredTaxAssetsNet" order="10" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_DeferredTaxAssetsValuationAllowance" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DeferredTaxAssetsValuationAllowance"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfDeferredTaxAssetsAbstract" xlink:to="us-gaap_DeferredTaxAssetsValuationAllowance" order="11" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_DeferredTaxAssetNetOfValuationAllowance" xlink:href="oprx-20211231.xsd#oprx_DeferredTaxAssetNetOfValuationAllowance"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ScheduleOfDeferredTaxAssetsAbstract" xlink:to="oprx_DeferredTaxAssetNetOfValuationAllowance" order="12" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/OrganizationandNatureofBusinessDetails">
    <loc xlink:type="locator" xlink:label="us-gaap_OrganizationConsolidationAndPresentationOfFinancialStatementsAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OrganizationConsolidationAndPresentationOfFinancialStatementsAbstract"/>
    <loc xlink:type="locator" xlink:label="oprx_USHealthcareProvidersPercentage" xlink:href="oprx-20211231.xsd#oprx_USHealthcareProvidersPercentage"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_OrganizationConsolidationAndPresentationOfFinancialStatementsAbstract" xlink:to="oprx_USHealthcareProvidersPercentage" order="0" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/SummaryofSignificantAccountingPoliciesDetails">
    <loc xlink:type="locator" xlink:label="oprx_SummaryofSignificantAccountingPoliciesDetailsLineItems" xlink:href="oprx-20211231.xsd#oprx_SummaryofSignificantAccountingPoliciesDetailsLineItems"/>
    <loc xlink:type="locator" xlink:label="oprx_SummaryofSignificantAccountingPoliciesDetailsTable" xlink:href="oprx-20211231.xsd#oprx_SummaryofSignificantAccountingPoliciesDetailsTable"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="oprx_SummaryofSignificantAccountingPoliciesDetailsLineItems" xlink:to="oprx_SummaryofSignificantAccountingPoliciesDetailsTable" order="0" xbrldt:contextElement="segment" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_AwardTypeAxis" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_AwardTypeAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="oprx_SummaryofSignificantAccountingPoliciesDetailsTable" xlink:to="us-gaap_AwardTypeAxis" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_AwardTypeAxis" xlink:to="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain_0" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_AwardTypeAxis" xlink:to="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain_0" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_RestrictedStockMember" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_RestrictedStockMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="us-gaap_RestrictedStockMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ProvisionForDoubtfulAccounts" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ProvisionForDoubtfulAccounts"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_SummaryofSignificantAccountingPoliciesDetailsLineItems" xlink:to="us-gaap_ProvisionForDoubtfulAccounts" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_AllowanceForDoubtfulAccountsReceivableCurrent" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_AllowanceForDoubtfulAccountsReceivableCurrent"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_SummaryofSignificantAccountingPoliciesDetailsLineItems" xlink:to="us-gaap_AllowanceForDoubtfulAccountsReceivableCurrent" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_UnbilledContractsReceivable" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_UnbilledContractsReceivable"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_SummaryofSignificantAccountingPoliciesDetailsLineItems" xlink:to="us-gaap_UnbilledContractsReceivable" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_EffectiveIncomeTaxRateReconciliationTaxSettlements" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_EffectiveIncomeTaxRateReconciliationTaxSettlements"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_SummaryofSignificantAccountingPoliciesDetailsLineItems" xlink:to="us-gaap_EffectiveIncomeTaxRateReconciliationTaxSettlements" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_CashFDICInsuredAmount" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CashFDICInsuredAmount"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_SummaryofSignificantAccountingPoliciesDetailsLineItems" xlink:to="us-gaap_CashFDICInsuredAmount" order="5" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareAmount" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareAmount"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_SummaryofSignificantAccountingPoliciesDetailsLineItems" xlink:to="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareAmount" order="6" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_WeightedAverageNumberOfSharesRestrictedStock" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_WeightedAverageNumberOfSharesRestrictedStock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_SummaryofSignificantAccountingPoliciesDetailsLineItems" xlink:to="us-gaap_WeightedAverageNumberOfSharesRestrictedStock" order="7" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/PropertyandEquipmentDetails">
    <loc xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PropertyPlantAndEquipmentAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_Depreciation" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_Depreciation"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PropertyPlantAndEquipmentAbstract" xlink:to="us-gaap_Depreciation" order="0" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/IntangibleAssetsDetails">
    <loc xlink:type="locator" xlink:label="us-gaap_GoodwillAndIntangibleAssetsDisclosureAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_GoodwillAndIntangibleAssetsDisclosureAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_AdjustmentForAmortization" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_AdjustmentForAmortization"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_GoodwillAndIntangibleAssetsDisclosureAbstract" xlink:to="us-gaap_AdjustmentForAmortization" order="0" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/DeferredRevenueDetails">
    <loc xlink:type="locator" xlink:label="oprx_DeferredRevenueDetailsLineItems" xlink:href="oprx-20211231.xsd#oprx_DeferredRevenueDetailsLineItems"/>
    <loc xlink:type="locator" xlink:label="oprx_DeferredRevenueDetailsTable" xlink:href="oprx-20211231.xsd#oprx_DeferredRevenueDetailsTable"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="oprx_DeferredRevenueDetailsLineItems" xlink:to="oprx_DeferredRevenueDetailsTable" order="0" xbrldt:contextElement="segment" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_DeferredRevenueAdditions" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DeferredRevenueAdditions"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_DeferredRevenueDetailsLineItems" xlink:to="us-gaap_DeferredRevenueAdditions" order="1" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/RelatedPartyTransactionsDetails">
    <loc xlink:type="locator" xlink:label="us-gaap_RelatedPartyTransactionsAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_RelatedPartyTransactionsAbstract"/>
    <loc xlink:type="locator" xlink:label="oprx_OptionsGrantedToAcquireExclusivePatentRights" xlink:href="oprx-20211231.xsd#oprx_OptionsGrantedToAcquireExclusivePatentRights"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_RelatedPartyTransactionsAbstract" xlink:to="oprx_OptionsGrantedToAcquireExclusivePatentRights" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_RevenueFromRelatedParties" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_RevenueFromRelatedParties"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_RelatedPartyTransactionsAbstract" xlink:to="us-gaap_RevenueFromRelatedParties" order="1" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/ContingentPurchasePriceDetails">
    <loc xlink:type="locator" xlink:label="oprx_ContingentPurchasePriceDetailsLineItems" xlink:href="oprx-20211231.xsd#oprx_ContingentPurchasePriceDetailsLineItems"/>
    <loc xlink:type="locator" xlink:label="oprx_ContingentPurchasePriceDetailsTable" xlink:href="oprx-20211231.xsd#oprx_ContingentPurchasePriceDetailsTable"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="oprx_ContingentPurchasePriceDetailsLineItems" xlink:to="oprx_ContingentPurchasePriceDetailsTable" order="0" xbrldt:contextElement="segment" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_RelatedPartyTransactionAxis" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_RelatedPartyTransactionAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="oprx_ContingentPurchasePriceDetailsTable" xlink:to="us-gaap_RelatedPartyTransactionAxis" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_RelatedPartyTransactionDomain" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_RelatedPartyTransactionDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_RelatedPartyTransactionAxis" xlink:to="us-gaap_RelatedPartyTransactionDomain" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_RelatedPartyTransactionDomain_0" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_RelatedPartyTransactionDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_RelatedPartyTransactionAxis" xlink:to="us-gaap_RelatedPartyTransactionDomain_0" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_RMDYHealthShareholdersMember" xlink:href="oprx-20211231.xsd#oprx_RMDYHealthShareholdersMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_RelatedPartyTransactionDomain" xlink:to="oprx_RMDYHealthShareholdersMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_ContingentPaymentInCash" xlink:href="oprx-20211231.xsd#oprx_ContingentPaymentInCash"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ContingentPurchasePriceDetailsLineItems" xlink:to="oprx_ContingentPaymentInCash" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_ContingentEquityFairValueDisclosure" xlink:href="oprx-20211231.xsd#oprx_ContingentEquityFairValueDisclosure"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ContingentPurchasePriceDetailsLineItems" xlink:to="oprx_ContingentEquityFairValueDisclosure" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_MinimumPaymentForContingent" xlink:href="oprx-20211231.xsd#oprx_MinimumPaymentForContingent"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ContingentPurchasePriceDetailsLineItems" xlink:to="oprx_MinimumPaymentForContingent" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_FairValueOfRiskFreeRateOfReturn" xlink:href="oprx-20211231.xsd#oprx_FairValueOfRiskFreeRateOfReturn"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ContingentPurchasePriceDetailsLineItems" xlink:to="oprx_FairValueOfRiskFreeRateOfReturn" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_FairValueOfTerm" xlink:href="oprx-20211231.xsd#oprx_FairValueOfTerm"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ContingentPurchasePriceDetailsLineItems" xlink:to="oprx_FairValueOfTerm" order="5" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_FairValueOfVolatility" xlink:href="oprx-20211231.xsd#oprx_FairValueOfVolatility"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ContingentPurchasePriceDetailsLineItems" xlink:to="oprx_FairValueOfVolatility" order="6" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_PaymentOfShareholderLiability" xlink:href="oprx-20211231.xsd#oprx_PaymentOfShareholderLiability"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ContingentPurchasePriceDetailsLineItems" xlink:to="oprx_PaymentOfShareholderLiability" order="7" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_PaymentForLiability" xlink:href="oprx-20211231.xsd#oprx_PaymentForLiability"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_ContingentPurchasePriceDetailsLineItems" xlink:to="oprx_PaymentForLiability" order="8" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/StockholdersEquityDetails">
    <loc xlink:type="locator" xlink:label="oprx_StockholdersEquityDetailsLineItems" xlink:href="oprx-20211231.xsd#oprx_StockholdersEquityDetailsLineItems"/>
    <loc xlink:type="locator" xlink:label="oprx_StockholdersEquityDetailsTable" xlink:href="oprx-20211231.xsd#oprx_StockholdersEquityDetailsTable"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="oprx_StockholdersEquityDetailsLineItems" xlink:to="oprx_StockholdersEquityDetailsTable" order="0" xbrldt:contextElement="segment" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_RelatedPartyTransactionAxis" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_RelatedPartyTransactionAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="oprx_StockholdersEquityDetailsTable" xlink:to="us-gaap_RelatedPartyTransactionAxis" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_RelatedPartyTransactionDomain" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_RelatedPartyTransactionDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_RelatedPartyTransactionAxis" xlink:to="us-gaap_RelatedPartyTransactionDomain" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_RelatedPartyTransactionDomain_0" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_RelatedPartyTransactionDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_RelatedPartyTransactionAxis" xlink:to="us-gaap_RelatedPartyTransactionDomain_0" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_StatementEquityComponentsAxis" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StatementEquityComponentsAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="oprx_StockholdersEquityDetailsTable" xlink:to="us-gaap_StatementEquityComponentsAxis" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_EquityComponentDomain" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_EquityComponentDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_StatementEquityComponentsAxis" xlink:to="us-gaap_EquityComponentDomain" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_EquityComponentDomain_0" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_EquityComponentDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_StatementEquityComponentsAxis" xlink:to="us-gaap_EquityComponentDomain_0" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_PreferredStockMember" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PreferredStockMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EquityComponentDomain" xlink:to="us-gaap_PreferredStockMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_CommonStockMember" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CommonStockMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EquityComponentDomain" xlink:to="us-gaap_CommonStockMember" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_DirectorMember" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_DirectorMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_RelatedPartyTransactionDomain" xlink:to="srt_DirectorMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_PreferredStockSharesAuthorized" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PreferredStockSharesAuthorized"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_StockholdersEquityDetailsLineItems" xlink:to="us-gaap_PreferredStockSharesAuthorized" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_CommonStockSharesAuthorized" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CommonStockSharesAuthorized"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_StockholdersEquityDetailsLineItems" xlink:to="us-gaap_CommonStockSharesAuthorized" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_CommonStockSharesIssued" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CommonStockSharesIssued"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_StockholdersEquityDetailsLineItems" xlink:to="us-gaap_CommonStockSharesIssued" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_CommonStockSharesOutstanding" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CommonStockSharesOutstanding"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_StockholdersEquityDetailsLineItems" xlink:to="us-gaap_CommonStockSharesOutstanding" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_StockIssuedDuringPeriodSharesNewIssues" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StockIssuedDuringPeriodSharesNewIssues"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_StockholdersEquityDetailsLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodSharesNewIssues" order="5" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_StockIssuedDuringPeriodValueNewIssues" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StockIssuedDuringPeriodValueNewIssues"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_StockholdersEquityDetailsLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodValueNewIssues" order="6" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_IssuanceOfCommonStockExerciseValue" xlink:href="oprx-20211231.xsd#oprx_IssuanceOfCommonStockExerciseValue"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_StockholdersEquityDetailsLineItems" xlink:to="oprx_IssuanceOfCommonStockExerciseValue" order="7" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_PaymentsToAdvisorsAndLegalFees" xlink:href="oprx-20211231.xsd#oprx_PaymentsToAdvisorsAndLegalFees"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_StockholdersEquityDetailsLineItems" xlink:to="oprx_PaymentsToAdvisorsAndLegalFees" order="8" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_StockIssuedDuringPeriodSharesOther" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StockIssuedDuringPeriodSharesOther"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_StockholdersEquityDetailsLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodSharesOther" order="9" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_GrossProceedsOfCommonStockAmount" xlink:href="oprx-20211231.xsd#oprx_GrossProceedsOfCommonStockAmount"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_StockholdersEquityDetailsLineItems" xlink:to="oprx_GrossProceedsOfCommonStockAmount" order="10" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/StockCompensationDetails">
    <loc xlink:type="locator" xlink:label="oprx_StockCompensationDetailsLineItems" xlink:href="oprx-20211231.xsd#oprx_StockCompensationDetailsLineItems"/>
    <loc xlink:type="locator" xlink:label="oprx_StockCompensationDetailsTable" xlink:href="oprx-20211231.xsd#oprx_StockCompensationDetailsTable"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="oprx_StockCompensationDetailsLineItems" xlink:to="oprx_StockCompensationDetailsTable" order="0" xbrldt:contextElement="segment" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_AwardTypeAxis" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_AwardTypeAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="oprx_StockCompensationDetailsTable" xlink:to="us-gaap_AwardTypeAxis" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_AwardTypeAxis" xlink:to="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain_0" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_AwardTypeAxis" xlink:to="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain_0" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_TitleOfIndividualAxis" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_TitleOfIndividualAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="oprx_StockCompensationDetailsTable" xlink:to="srt_TitleOfIndividualAxis" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_TitleOfIndividualWithRelationshipToEntityDomain" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_TitleOfIndividualWithRelationshipToEntityDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_TitleOfIndividualAxis" xlink:to="srt_TitleOfIndividualWithRelationshipToEntityDomain" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_TitleOfIndividualWithRelationshipToEntityDomain_0" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_TitleOfIndividualWithRelationshipToEntityDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="srt_TitleOfIndividualAxis" xlink:to="srt_TitleOfIndividualWithRelationshipToEntityDomain_0" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_FinancialInstrumentAxis" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FinancialInstrumentAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="oprx_StockCompensationDetailsTable" xlink:to="us-gaap_FinancialInstrumentAxis" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_TransfersAndServicingOfFinancialInstrumentsTypesOfFinancialInstrumentsDomain" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_TransfersAndServicingOfFinancialInstrumentsTypesOfFinancialInstrumentsDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_FinancialInstrumentAxis" xlink:to="us-gaap_TransfersAndServicingOfFinancialInstrumentsTypesOfFinancialInstrumentsDomain" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_TransfersAndServicingOfFinancialInstrumentsTypesOfFinancialInstrumentsDomain_0" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_TransfersAndServicingOfFinancialInstrumentsTypesOfFinancialInstrumentsDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_FinancialInstrumentAxis" xlink:to="us-gaap_TransfersAndServicingOfFinancialInstrumentsTypesOfFinancialInstrumentsDomain_0" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeAxis" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="oprx_StockCompensationDetailsTable" xlink:to="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeAxis" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeAxis" xlink:to="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain_0" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeAxis" xlink:to="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain_0" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_StatementEquityComponentsAxis" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StatementEquityComponentsAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="oprx_StockCompensationDetailsTable" xlink:to="us-gaap_StatementEquityComponentsAxis" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_EquityComponentDomain" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_EquityComponentDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_StatementEquityComponentsAxis" xlink:to="us-gaap_EquityComponentDomain" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_EquityComponentDomain_0" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_EquityComponentDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_StatementEquityComponentsAxis" xlink:to="us-gaap_EquityComponentDomain_0" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_CommonStockMember" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CommonStockMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EquityComponentDomain" xlink:to="us-gaap_CommonStockMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_OptionMember" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OptionMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_TransfersAndServicingOfFinancialInstrumentsTypesOfFinancialInstrumentsDomain" xlink:to="us-gaap_OptionMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_MinimumMember" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_MinimumMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain" xlink:to="srt_MinimumMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_MaximumMember" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_MaximumMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain" xlink:to="srt_MaximumMember" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_StockCompensationPlanMember" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StockCompensationPlanMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="us-gaap_StockCompensationPlanMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_RestrictedStockMember" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_RestrictedStockMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="us-gaap_RestrictedStockMember" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_BoardOfDirectorsChairmanMember" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_BoardOfDirectorsChairmanMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_TitleOfIndividualWithRelationshipToEntityDomain" xlink:to="srt_BoardOfDirectorsChairmanMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_StockCompensationDetailsLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_ShareBasedCompensationArrangementBySharesBasedPaymentsAwardOptionsExercisableNumber" xlink:href="oprx-20211231.xsd#oprx_ShareBasedCompensationArrangementBySharesBasedPaymentsAwardOptionsExercisableNumber"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_StockCompensationDetailsLineItems" xlink:to="oprx_ShareBasedCompensationArrangementBySharesBasedPaymentsAwardOptionsExercisableNumber" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_StockIssuedDuringPeriodSharesRestrictedStockAwardGross" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StockIssuedDuringPeriodSharesRestrictedStockAwardGross"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_StockCompensationDetailsLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodSharesRestrictedStockAwardGross" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_SharesIssued" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SharesIssued"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_StockCompensationDetailsLineItems" xlink:to="us-gaap_SharesIssued" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_SharesOfCommonStockUnderlyingRestrictedStockUnitAwards" xlink:href="oprx-20211231.xsd#oprx_SharesOfCommonStockUnderlyingRestrictedStockUnitAwards"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_StockCompensationDetailsLineItems" xlink:to="oprx_SharesOfCommonStockUnderlyingRestrictedStockUnitAwards" order="5" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_StockCompensationDetailsLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant" order="6" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_PercentageOfFairMarketValueOfCommonstock" xlink:href="oprx-20211231.xsd#oprx_PercentageOfFairMarketValueOfCommonstock"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_StockCompensationDetailsLineItems" xlink:to="oprx_PercentageOfFairMarketValueOfCommonstock" order="7" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_DeferredCompensationArrangementWithIndividualCompensationExpense" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DeferredCompensationArrangementWithIndividualCompensationExpense"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_StockCompensationDetailsLineItems" xlink:to="us-gaap_DeferredCompensationArrangementWithIndividualCompensationExpense" order="8" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_StockOptionPlanExpense" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StockOptionPlanExpense"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_StockCompensationDetailsLineItems" xlink:to="us-gaap_StockOptionPlanExpense" order="9" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsVestedAndExpectedToVestOutstandingWeightedAverageRemainingContractualTerm1" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsVestedAndExpectedToVestOutstandingWeightedAverageRemainingContractualTerm1"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_StockCompensationDetailsLineItems" xlink:to="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsVestedAndExpectedToVestOutstandingWeightedAverageRemainingContractualTerm1" order="10" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_StockIssuedDuringPeriodValueRestrictedStockAwardGross" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StockIssuedDuringPeriodValueRestrictedStockAwardGross"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_StockCompensationDetailsLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodValueRestrictedStockAwardGross" order="11" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsVestedAndExpectedToVestExercisableWeightedAverageRemainingContractualTerm1" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsVestedAndExpectedToVestExercisableWeightedAverageRemainingContractualTerm1"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_StockCompensationDetailsLineItems" xlink:to="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsVestedAndExpectedToVestExercisableWeightedAverageRemainingContractualTerm1" order="12" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_EmployeeServiceShareBasedCompensationAllocationOfRecognizedPeriodCostsCapitalizedAmount" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_EmployeeServiceShareBasedCompensationAllocationOfRecognizedPeriodCostsCapitalizedAmount"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_StockCompensationDetailsLineItems" xlink:to="us-gaap_EmployeeServiceShareBasedCompensationAllocationOfRecognizedPeriodCostsCapitalizedAmount" order="13" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_SharesBasedCompensationArrangementBySharesBasedPaymentAwardOptionsOutstandingWeightedAverageRemainingContractualTerm2" xlink:href="oprx-20211231.xsd#oprx_SharesBasedCompensationArrangementBySharesBasedPaymentAwardOptionsOutstandingWeightedAverageRemainingContractualTerm2"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_StockCompensationDetailsLineItems" xlink:to="oprx_SharesBasedCompensationArrangementBySharesBasedPaymentAwardOptionsOutstandingWeightedAverageRemainingContractualTerm2" order="14" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_RestrictedStockUnitsIssued" xlink:href="oprx-20211231.xsd#oprx_RestrictedStockUnitsIssued"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_StockCompensationDetailsLineItems" xlink:to="oprx_RestrictedStockUnitsIssued" order="15" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_VestedPriceUnitsDescription" xlink:href="oprx-20211231.xsd#oprx_VestedPriceUnitsDescription"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_StockCompensationDetailsLineItems" xlink:to="oprx_VestedPriceUnitsDescription" order="16" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/LeasesDetails">
    <loc xlink:type="locator" xlink:label="oprx_LeasesDetailsLineItems" xlink:href="oprx-20211231.xsd#oprx_LeasesDetailsLineItems"/>
    <loc xlink:type="locator" xlink:label="oprx_LeasesDetailsTable" xlink:href="oprx-20211231.xsd#oprx_LeasesDetailsTable"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="oprx_LeasesDetailsLineItems" xlink:to="oprx_LeasesDetailsTable" order="0" xbrldt:contextElement="segment" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_RangeAxis" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_RangeAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="oprx_LeasesDetailsTable" xlink:to="srt_RangeAxis" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_RangeMember" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_RangeMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_RangeAxis" xlink:to="srt_RangeMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_RangeMember_0" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_RangeMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="srt_RangeAxis" xlink:to="srt_RangeMember_0" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_MinimumMember" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_MinimumMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MinimumMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_MaximumMember" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_MaximumMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MaximumMember" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_OperatingLeasesExpiresPeriod" xlink:href="oprx-20211231.xsd#oprx_OperatingLeasesExpiresPeriod"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_LeasesDetailsLineItems" xlink:to="oprx_OperatingLeasesExpiresPeriod" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_OperatingLeasesRentPayable" xlink:href="oprx-20211231.xsd#oprx_OperatingLeasesRentPayable"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_LeasesDetailsLineItems" xlink:to="oprx_OperatingLeasesRentPayable" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_LesseeOperatingLeaseDescription" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_LesseeOperatingLeaseDescription"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_LeasesDetailsLineItems" xlink:to="us-gaap_LesseeOperatingLeaseDescription" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_OperatingLeaseWeightedAverageRemainingLeaseTerm1" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OperatingLeaseWeightedAverageRemainingLeaseTerm1"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_LeasesDetailsLineItems" xlink:to="us-gaap_OperatingLeaseWeightedAverageRemainingLeaseTerm1" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_OperatingLeaseWeightedAverageDiscountRatePercent" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OperatingLeaseWeightedAverageDiscountRatePercent"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_LeasesDetailsLineItems" xlink:to="us-gaap_OperatingLeaseWeightedAverageDiscountRatePercent" order="5" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_MeasurementOfLeaseLiabilities" xlink:href="oprx-20211231.xsd#oprx_MeasurementOfLeaseLiabilities"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_LeasesDetailsLineItems" xlink:to="oprx_MeasurementOfLeaseLiabilities" order="6" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_OperatingLeaseLeaseIncomeLeasePayments" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OperatingLeaseLeaseIncomeLeasePayments"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_LeasesDetailsLineItems" xlink:to="us-gaap_OperatingLeaseLeaseIncomeLeasePayments" order="7" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_OperatingLeaseRightOfUseAssetAmortizationExpense" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OperatingLeaseRightOfUseAssetAmortizationExpense"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_LeasesDetailsLineItems" xlink:to="us-gaap_OperatingLeaseRightOfUseAssetAmortizationExpense" order="8" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/MajorCustomersandVendorsDetails">
    <loc xlink:type="locator" xlink:label="oprx_MajorCustomersandVendorsDetailsLineItems" xlink:href="oprx-20211231.xsd#oprx_MajorCustomersandVendorsDetailsLineItems"/>
    <loc xlink:type="locator" xlink:label="oprx_MajorCustomersandVendorsDetailsTable" xlink:href="oprx-20211231.xsd#oprx_MajorCustomersandVendorsDetailsTable"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="oprx_MajorCustomersandVendorsDetailsLineItems" xlink:to="oprx_MajorCustomersandVendorsDetailsTable" order="0" xbrldt:contextElement="segment" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_RelatedPartyTransactionAxis" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_RelatedPartyTransactionAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="oprx_MajorCustomersandVendorsDetailsTable" xlink:to="us-gaap_RelatedPartyTransactionAxis" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_RelatedPartyTransactionDomain" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_RelatedPartyTransactionDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_RelatedPartyTransactionAxis" xlink:to="us-gaap_RelatedPartyTransactionDomain" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_RelatedPartyTransactionDomain_0" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_RelatedPartyTransactionDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_RelatedPartyTransactionAxis" xlink:to="us-gaap_RelatedPartyTransactionDomain_0" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_MajorCustomersAxis" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_MajorCustomersAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="oprx_MajorCustomersandVendorsDetailsTable" xlink:to="srt_MajorCustomersAxis" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_NameOfMajorCustomerDomain" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_NameOfMajorCustomerDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_MajorCustomersAxis" xlink:to="srt_NameOfMajorCustomerDomain" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_NameOfMajorCustomerDomain_0" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_NameOfMajorCustomerDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="srt_MajorCustomersAxis" xlink:to="srt_NameOfMajorCustomerDomain_0" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_OtherCustomerMember" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OtherCustomerMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_NameOfMajorCustomerDomain" xlink:to="us-gaap_OtherCustomerMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_CustomerOneMember" xlink:href="oprx-20211231.xsd#oprx_CustomerOneMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_NameOfMajorCustomerDomain" xlink:to="oprx_CustomerOneMember" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_CustomerTwoMember" xlink:href="oprx-20211231.xsd#oprx_CustomerTwoMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_NameOfMajorCustomerDomain" xlink:to="oprx_CustomerTwoMember" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_OneEntitiesMember" xlink:href="oprx-20211231.xsd#oprx_OneEntitiesMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_NameOfMajorCustomerDomain" xlink:to="oprx_OneEntitiesMember" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_TwoEntitiesMember" xlink:href="oprx-20211231.xsd#oprx_TwoEntitiesMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_NameOfMajorCustomerDomain" xlink:to="oprx_TwoEntitiesMember" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_CustomerThreeMember" xlink:href="oprx-20211231.xsd#oprx_CustomerThreeMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_NameOfMajorCustomerDomain" xlink:to="oprx_CustomerThreeMember" order="5" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_CustomerFourMember" xlink:href="oprx-20211231.xsd#oprx_CustomerFourMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_NameOfMajorCustomerDomain" xlink:to="oprx_CustomerFourMember" order="6" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_KeyPartnersMember" xlink:href="oprx-20211231.xsd#oprx_KeyPartnersMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_NameOfMajorCustomerDomain" xlink:to="oprx_KeyPartnersMember" order="7" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_AccountsReceivableMember" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_AccountsReceivableMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_RelatedPartyTransactionDomain" xlink:to="us-gaap_AccountsReceivableMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_ConcentrationRiskPercentage" xlink:href="oprx-20211231.xsd#oprx_ConcentrationRiskPercentage"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_MajorCustomersandVendorsDetailsLineItems" xlink:to="oprx_ConcentrationRiskPercentage" order="1" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/IncomeTaxesDetails">
    <loc xlink:type="locator" xlink:label="us-gaap_IncomeTaxDisclosureAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_IncomeTaxDisclosureAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_OperatingLossCarryforwardsLimitationsOnUse" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OperatingLossCarryforwardsLimitationsOnUse"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeTaxDisclosureAbstract" xlink:to="us-gaap_OperatingLossCarryforwardsLimitationsOnUse" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_EffectiveIncomeTaxRateContinuingOperations" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_EffectiveIncomeTaxRateContinuingOperations"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeTaxDisclosureAbstract" xlink:to="us-gaap_EffectiveIncomeTaxRateContinuingOperations" order="1" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/CommitmentsandContingentLiabilitiesDetails">
    <loc xlink:type="locator" xlink:label="oprx_CommitmentsandContingentLiabilitiesDetailsLineItems" xlink:href="oprx-20211231.xsd#oprx_CommitmentsandContingentLiabilitiesDetailsLineItems"/>
    <loc xlink:type="locator" xlink:label="oprx_CommitmentsandContingentLiabilitiesDetailsTable" xlink:href="oprx-20211231.xsd#oprx_CommitmentsandContingentLiabilitiesDetailsTable"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="oprx_CommitmentsandContingentLiabilitiesDetailsLineItems" xlink:to="oprx_CommitmentsandContingentLiabilitiesDetailsTable" order="0" xbrldt:contextElement="segment" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_StatementScenarioAxis" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_StatementScenarioAxis"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="oprx_CommitmentsandContingentLiabilitiesDetailsTable" xlink:to="srt_StatementScenarioAxis" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_ScenarioUnspecifiedDomain" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_ScenarioUnspecifiedDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_StatementScenarioAxis" xlink:to="srt_ScenarioUnspecifiedDomain" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_ScenarioUnspecifiedDomain_0" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_ScenarioUnspecifiedDomain"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="srt_StatementScenarioAxis" xlink:to="srt_ScenarioUnspecifiedDomain_0" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="srt_ScenarioForecastMember" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_ScenarioForecastMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_ScenarioUnspecifiedDomain" xlink:to="srt_ScenarioForecastMember" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_UnderpaymentPercentage" xlink:href="oprx-20211231.xsd#oprx_UnderpaymentPercentage"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_CommitmentsandContingentLiabilitiesDetailsLineItems" xlink:to="oprx_UnderpaymentPercentage" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_FutureMinimumPayments" xlink:href="oprx-20211231.xsd#oprx_FutureMinimumPayments"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_CommitmentsandContingentLiabilitiesDetailsLineItems" xlink:to="oprx_FutureMinimumPayments" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_MinimumPaymentsDue" xlink:href="oprx-20211231.xsd#oprx_MinimumPaymentsDue"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="oprx_CommitmentsandContingentLiabilitiesDetailsLineItems" xlink:to="oprx_MinimumPaymentsDue" order="3" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/RetirementPlanDetails">
    <loc xlink:type="locator" xlink:label="us-gaap_CompensationAndRetirementDisclosureAbstract" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CompensationAndRetirementDisclosureAbstract"/>
    <loc xlink:type="locator" xlink:label="us-gaap_DefinedContributionPlanCostRecognized" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DefinedContributionPlanCostRecognized"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_CompensationAndRetirementDisclosureAbstract" xlink:to="us-gaap_DefinedContributionPlanCostRecognized" order="0" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="us-gaap_DescriptionOfDefinedContributionPensionAndOtherPostretirementPlans" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DescriptionOfDefinedContributionPensionAndOtherPostretirementPlans"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_CompensationAndRetirementDisclosureAbstract" xlink:to="us-gaap_DescriptionOfDefinedContributionPensionAndOtherPostretirementPlans" order="1" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:type="extended" xlink:role="http://www.optimizerx.com/role/DocumentAndEntityInformation">
    <loc xlink:type="locator" xlink:label="dei_DocumentInformationLineItems" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_DocumentInformationLineItems"/>
    <loc xlink:type="locator" xlink:label="dei_DocumentInformationTable" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_DocumentInformationTable"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_DocumentInformationTable" order="0" xbrldt:contextElement="segment" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_EntityRegistrantName" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityRegistrantName"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_EntityRegistrantName" order="1" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_TradingSymbol" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_TradingSymbol"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_TradingSymbol" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_DocumentType" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_DocumentType"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_DocumentType" order="3" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_CurrentFiscalYearEndDate" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_CurrentFiscalYearEndDate"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_CurrentFiscalYearEndDate" order="4" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_EntityCommonStockSharesOutstanding" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityCommonStockSharesOutstanding"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_EntityCommonStockSharesOutstanding" order="5" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_EntityPublicFloat" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityPublicFloat"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_EntityPublicFloat" order="6" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_AmendmentFlag" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_AmendmentFlag"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_AmendmentFlag" order="7" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_AmendmentDescription" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_AmendmentDescription"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_AmendmentDescription" order="8" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_EntityCentralIndexKey" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityCentralIndexKey"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_EntityCentralIndexKey" order="9" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_EntityCurrentReportingStatus" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityCurrentReportingStatus"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_EntityCurrentReportingStatus" order="10" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_EntityVoluntaryFilers" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityVoluntaryFilers"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_EntityVoluntaryFilers" order="11" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_EntityFilerCategory" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityFilerCategory"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_EntityFilerCategory" order="12" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_EntityWellKnownSeasonedIssuer" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityWellKnownSeasonedIssuer"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_EntityWellKnownSeasonedIssuer" order="13" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_DocumentPeriodEndDate" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_DocumentPeriodEndDate"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_DocumentPeriodEndDate" order="14" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_DocumentFiscalYearFocus" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_DocumentFiscalYearFocus"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_DocumentFiscalYearFocus" order="15" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_DocumentFiscalPeriodFocus" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_DocumentFiscalPeriodFocus"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_DocumentFiscalPeriodFocus" order="16" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_EntitySmallBusiness" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntitySmallBusiness"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_EntitySmallBusiness" order="17" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_EntityEmergingGrowthCompany" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityEmergingGrowthCompany"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_EntityEmergingGrowthCompany" order="18" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_EntityShellCompany" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityShellCompany"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_EntityShellCompany" order="19" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_IcfrAuditorAttestationFlag" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_IcfrAuditorAttestationFlag"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_IcfrAuditorAttestationFlag" order="20" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_DocumentAnnualReport" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_DocumentAnnualReport"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_DocumentAnnualReport" order="21" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_DocumentTransitionReport" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_DocumentTransitionReport"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_DocumentTransitionReport" order="22" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_EntityFileNumber" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityFileNumber"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_EntityFileNumber" order="23" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_EntityIncorporationStateCountryCode" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityIncorporationStateCountryCode"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_EntityIncorporationStateCountryCode" order="24" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_EntityTaxIdentificationNumber" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityTaxIdentificationNumber"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_EntityTaxIdentificationNumber" order="25" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_EntityAddressAddressLine1" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityAddressAddressLine1"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_EntityAddressAddressLine1" order="26" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_EntityAddressAddressLine2" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityAddressAddressLine2"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_EntityAddressAddressLine2" order="27" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_EntityAddressCityOrTown" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityAddressCityOrTown"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_EntityAddressCityOrTown" order="28" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_EntityAddressStateOrProvince" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityAddressStateOrProvince"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_EntityAddressStateOrProvince" order="29" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_EntityAddressPostalZipCode" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityAddressPostalZipCode"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_EntityAddressPostalZipCode" order="30" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_CityAreaCode" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_CityAreaCode"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_CityAreaCode" order="31" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_LocalPhoneNumber" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_LocalPhoneNumber"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_LocalPhoneNumber" order="32" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_Security12bTitle" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_Security12bTitle"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_Security12bTitle" order="33" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_SecurityExchangeName" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_SecurityExchangeName"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_SecurityExchangeName" order="34" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_AuditorFirmId" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_AuditorFirmId"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_AuditorFirmId" order="35" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_EntityInteractiveDataCurrent" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityInteractiveDataCurrent"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_EntityInteractiveDataCurrent" order="36" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_AuditorName" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_AuditorName"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_AuditorName" order="37" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="dei_AuditorLocation" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_AuditorLocation"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_DocumentInformationLineItems" xlink:to="dei_AuditorLocation" order="38" xbrldt:closed="true"/>
  </definitionLink>
</linkbase>
