<?xml version="1.0" encoding="UTF-8" ?>
<linkbase xmlns="http://www.xbrl.org/2003/linkbase" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:xlink="http://www.w3.org/1999/xlink" xsi:schemaLocation="http://www.xbrl.org/2003/linkbase http://www.xbrl.org/2003/xbrl-linkbase-2003-12-31.xsd">
<roleRef xlink:type="simple" xlink:href="oprx-20171231.xsd#ConsolidatedBalanceSheets" roleURI="http://OPRX/role/ConsolidatedBalanceSheets"/>
<calculationLink xlink:type="extended" xlink:role="http://OPRX/role/ConsolidatedBalanceSheets">
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_AssetsCurrent" xlink:label="loc_us-gaap_AssetsCurrent" />
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_CashAndCashEquivalentsAtCarryingValue" xlink:label="loc_us-gaap_CashAndCashEquivalentsAtCarryingValue" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_AssetsCurrent" xlink:to="loc_us-gaap_CashAndCashEquivalentsAtCarryingValue" order="10" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_AccountsReceivableNetCurrent" xlink:label="loc_us-gaap_AccountsReceivableNetCurrent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_AssetsCurrent" xlink:to="loc_us-gaap_AccountsReceivableNetCurrent" order="20" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_AccountsReceivableRelatedPartiesCurrent" xlink:label="loc_us-gaap_AccountsReceivableRelatedPartiesCurrent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_AssetsCurrent" xlink:to="loc_us-gaap_AccountsReceivableRelatedPartiesCurrent" order="30" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_PrepaidExpenseCurrent" xlink:label="loc_us-gaap_PrepaidExpenseCurrent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_AssetsCurrent" xlink:to="loc_us-gaap_PrepaidExpenseCurrent" order="40" use="optional" weight="1"/>
</calculationLink>
<calculationLink xlink:type="extended" xlink:role="http://OPRX/role/ConsolidatedBalanceSheets">
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_OtherAssets" xlink:label="loc_us-gaap_OtherAssets" />
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_FiniteLivedIntangibleAssetsNet" xlink:label="loc_us-gaap_FiniteLivedIntangibleAssetsNet" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_OtherAssets" xlink:to="loc_us-gaap_FiniteLivedIntangibleAssetsNet" order="10" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_CapitalizedComputerSoftwareNet" xlink:label="loc_us-gaap_CapitalizedComputerSoftwareNet" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_OtherAssets" xlink:to="loc_us-gaap_CapitalizedComputerSoftwareNet" order="20" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_SecurityDeposit" xlink:label="loc_us-gaap_SecurityDeposit" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_OtherAssets" xlink:to="loc_us-gaap_SecurityDeposit" order="30" use="optional" weight="1"/>
</calculationLink>
<calculationLink xlink:type="extended" xlink:role="http://OPRX/role/ConsolidatedBalanceSheets">
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_Assets" xlink:label="loc_us-gaap_Assets" />
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_AssetsCurrent" xlink:label="loc_us-gaap_AssetsCurrent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_Assets" xlink:to="loc_us-gaap_AssetsCurrent" order="10" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_PropertyPlantAndEquipmentNet" xlink:label="loc_us-gaap_PropertyPlantAndEquipmentNet" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_Assets" xlink:to="loc_us-gaap_PropertyPlantAndEquipmentNet" order="20" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_OtherAssets" xlink:label="loc_us-gaap_OtherAssets" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_Assets" xlink:to="loc_us-gaap_OtherAssets" order="30" use="optional" weight="1"/>
</calculationLink>
<calculationLink xlink:type="extended" xlink:role="http://OPRX/role/ConsolidatedBalanceSheets">
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_LiabilitiesCurrent" xlink:label="loc_us-gaap_LiabilitiesCurrent" />
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_AccountsPayableTradeCurrent" xlink:label="loc_us-gaap_AccountsPayableTradeCurrent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_LiabilitiesCurrent" xlink:to="loc_us-gaap_AccountsPayableTradeCurrent" order="10" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_AccruedLiabilitiesCurrent" xlink:label="loc_us-gaap_AccruedLiabilitiesCurrent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_LiabilitiesCurrent" xlink:to="loc_us-gaap_AccruedLiabilitiesCurrent" order="20" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="oprx-20171231.xsd#oprx_RevenueSharePayableCurrent" xlink:label="loc_oprx_RevenueSharePayableCurrent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_LiabilitiesCurrent" xlink:to="loc_oprx_RevenueSharePayableCurrent" order="30" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="oprx-20171231.xsd#oprx_RevenueSharesPayableRelatedParty" xlink:label="loc_oprx_RevenueSharesPayableRelatedParty" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_LiabilitiesCurrent" xlink:to="loc_oprx_RevenueSharesPayableRelatedParty" order="40" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_DeferredRevenueCurrent" xlink:label="loc_us-gaap_DeferredRevenueCurrent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_LiabilitiesCurrent" xlink:to="loc_us-gaap_DeferredRevenueCurrent" order="50" use="optional" weight="1"/>
</calculationLink>
<calculationLink xlink:type="extended" xlink:role="http://OPRX/role/ConsolidatedBalanceSheets">
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_StockholdersEquity" xlink:label="loc_us-gaap_StockholdersEquity" />
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_PreferredStockValue" xlink:label="loc_us-gaap_PreferredStockValue" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_StockholdersEquity" xlink:to="loc_us-gaap_PreferredStockValue" order="10" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_CommonStockValue" xlink:label="loc_us-gaap_CommonStockValue" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_StockholdersEquity" xlink:to="loc_us-gaap_CommonStockValue" order="20" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_WarrantsAndRightsOutstanding" xlink:label="loc_us-gaap_WarrantsAndRightsOutstanding" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_StockholdersEquity" xlink:to="loc_us-gaap_WarrantsAndRightsOutstanding" order="30" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_AdditionalPaidInCapital" xlink:label="loc_us-gaap_AdditionalPaidInCapital" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_StockholdersEquity" xlink:to="loc_us-gaap_AdditionalPaidInCapital" order="40" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_RetainedEarningsAccumulatedDeficit" xlink:label="loc_us-gaap_RetainedEarningsAccumulatedDeficit" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_StockholdersEquity" xlink:to="loc_us-gaap_RetainedEarningsAccumulatedDeficit" order="50" use="optional" weight="1"/>
</calculationLink>
<calculationLink xlink:type="extended" xlink:role="http://OPRX/role/ConsolidatedBalanceSheets">
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_LiabilitiesAndStockholdersEquity" xlink:label="loc_us-gaap_LiabilitiesAndStockholdersEquity" />
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_LiabilitiesCurrent" xlink:label="loc_us-gaap_LiabilitiesCurrent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_LiabilitiesAndStockholdersEquity" xlink:to="loc_us-gaap_LiabilitiesCurrent" order="10" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_StockholdersEquity" xlink:label="loc_us-gaap_StockholdersEquity" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_LiabilitiesAndStockholdersEquity" xlink:to="loc_us-gaap_StockholdersEquity" order="20" use="optional" weight="1"/>
</calculationLink>
<roleRef xlink:type="simple" xlink:href="oprx-20171231.xsd#ConsolidatedStatementsOfOperations" roleURI="http://OPRX/role/ConsolidatedStatementsOfOperations"/>
<calculationLink xlink:type="extended" xlink:role="http://OPRX/role/ConsolidatedStatementsOfOperations">
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_Revenues" xlink:label="loc_us-gaap_Revenues" />
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_SalesRevenueNet" xlink:label="loc_us-gaap_SalesRevenueNet" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_Revenues" xlink:to="loc_us-gaap_SalesRevenueNet" order="10" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_RevenueFromRelatedParties" xlink:label="loc_us-gaap_RevenueFromRelatedParties" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_Revenues" xlink:to="loc_us-gaap_RevenueFromRelatedParties" order="20" use="optional" weight="1"/>
</calculationLink>
<calculationLink xlink:type="extended" xlink:role="http://OPRX/role/ConsolidatedStatementsOfOperations">
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_GrossProfit" xlink:label="loc_us-gaap_GrossProfit" />
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_Revenues" xlink:label="loc_us-gaap_Revenues" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_GrossProfit" xlink:to="loc_us-gaap_Revenues" order="10" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="oprx-20171231.xsd#oprx_RevenueShareExpense" xlink:label="loc_oprx_RevenueShareExpense" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_GrossProfit" xlink:to="loc_oprx_RevenueShareExpense" order="20" use="optional" weight="-1"/>
</calculationLink>
<calculationLink xlink:type="extended" xlink:role="http://OPRX/role/ConsolidatedStatementsOfOperations">
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_OperatingExpenses" xlink:label="loc_us-gaap_OperatingExpenses" />
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_AllocatedShareBasedCompensationExpense" xlink:label="loc_us-gaap_AllocatedShareBasedCompensationExpense" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_OperatingExpenses" xlink:to="loc_us-gaap_AllocatedShareBasedCompensationExpense" order="10" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_DepreciationAndAmortization" xlink:label="loc_us-gaap_DepreciationAndAmortization" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_OperatingExpenses" xlink:to="loc_us-gaap_DepreciationAndAmortization" order="20" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_LitigationSettlementExpense" xlink:label="loc_us-gaap_LitigationSettlementExpense" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_OperatingExpenses" xlink:to="loc_us-gaap_LitigationSettlementExpense" order="30" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_OtherGeneralAndAdministrativeExpense" xlink:label="loc_us-gaap_OtherGeneralAndAdministrativeExpense" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_OperatingExpenses" xlink:to="loc_us-gaap_OtherGeneralAndAdministrativeExpense" order="40" use="optional" weight="1"/>
</calculationLink>
<calculationLink xlink:type="extended" xlink:role="http://OPRX/role/ConsolidatedStatementsOfOperations">
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_OperatingIncomeLoss" xlink:label="loc_us-gaap_OperatingIncomeLoss" />
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_GrossProfit" xlink:label="loc_us-gaap_GrossProfit" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_OperatingIncomeLoss" xlink:to="loc_us-gaap_GrossProfit" order="10" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_OperatingExpenses" xlink:label="loc_us-gaap_OperatingExpenses" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_OperatingIncomeLoss" xlink:to="loc_us-gaap_OperatingExpenses" order="20" use="optional" weight="-1"/>
</calculationLink>
<calculationLink xlink:type="extended" xlink:role="http://OPRX/role/ConsolidatedStatementsOfOperations">
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_NonoperatingIncomeExpense" xlink:label="loc_us-gaap_NonoperatingIncomeExpense" />
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_InvestmentIncomeInterest" xlink:label="loc_us-gaap_InvestmentIncomeInterest" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NonoperatingIncomeExpense" xlink:to="loc_us-gaap_InvestmentIncomeInterest" order="10" use="optional" weight="1"/>
</calculationLink>
<calculationLink xlink:type="extended" xlink:role="http://OPRX/role/ConsolidatedStatementsOfOperations">
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" xlink:label="loc_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" />
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_OperatingIncomeLoss" xlink:label="loc_us-gaap_OperatingIncomeLoss" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" xlink:to="loc_us-gaap_OperatingIncomeLoss" order="10" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_NonoperatingIncomeExpense" xlink:label="loc_us-gaap_NonoperatingIncomeExpense" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" xlink:to="loc_us-gaap_NonoperatingIncomeExpense" order="20" use="optional" weight="1"/>
</calculationLink>
<calculationLink xlink:type="extended" xlink:role="http://OPRX/role/ConsolidatedStatementsOfOperations">
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_NetIncomeLoss" xlink:label="loc_us-gaap_NetIncomeLoss" />
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" xlink:label="loc_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetIncomeLoss" xlink:to="loc_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" order="10" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_IncomeTaxExpenseBenefit" xlink:label="loc_us-gaap_IncomeTaxExpenseBenefit" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetIncomeLoss" xlink:to="loc_us-gaap_IncomeTaxExpenseBenefit" order="20" use="optional" weight="-1"/>
</calculationLink>
<roleRef xlink:type="simple" xlink:href="oprx-20171231.xsd#ConsolidatedStatementsOfCashFlow" roleURI="http://OPRX/role/ConsolidatedStatementsOfCashFlow"/>
<calculationLink xlink:type="extended" xlink:role="http://OPRX/role/ConsolidatedStatementsOfCashFlow">
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:label="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" />
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_NetIncomeLoss" xlink:label="loc_us-gaap_NetIncomeLoss" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_us-gaap_NetIncomeLoss" order="10" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_DepreciationAndAmortization" xlink:label="loc_us-gaap_DepreciationAndAmortization" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_us-gaap_DepreciationAndAmortization" order="20" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_GainLossOnDispositionOfAssets1" xlink:label="loc_us-gaap_GainLossOnDispositionOfAssets1" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_us-gaap_GainLossOnDispositionOfAssets1" order="30" use="optional" weight="-1"/>
<loc xlink:type="locator" xlink:href="oprx-20171231.xsd#oprx_StockOptionsIssuedForServices" xlink:label="loc_oprx_StockOptionsIssuedForServices" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_oprx_StockOptionsIssuedForServices" order="40" use="optional" weight="-1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_ShareBasedCompensation" xlink:label="loc_us-gaap_ShareBasedCompensation" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_us-gaap_ShareBasedCompensation" order="50" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_IncreaseDecreaseInAccountsReceivable" xlink:label="loc_us-gaap_IncreaseDecreaseInAccountsReceivable" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_us-gaap_IncreaseDecreaseInAccountsReceivable" order="60" use="optional" weight="-1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_IncreaseDecreaseInAccountsReceivableRelatedParties" xlink:label="loc_us-gaap_IncreaseDecreaseInAccountsReceivableRelatedParties" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_us-gaap_IncreaseDecreaseInAccountsReceivableRelatedParties" order="70" use="optional" weight="-1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_IncreaseDecreaseInPrepaidExpense" xlink:label="loc_us-gaap_IncreaseDecreaseInPrepaidExpense" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_us-gaap_IncreaseDecreaseInPrepaidExpense" order="80" use="optional" weight="-1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_IncreaseDecreaseInAccountsPayable" xlink:label="loc_us-gaap_IncreaseDecreaseInAccountsPayable" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_us-gaap_IncreaseDecreaseInAccountsPayable" order="90" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="oprx-20171231.xsd#oprx_IncreaseDecreaseInRevenueSharePayable" xlink:label="loc_oprx_IncreaseDecreaseInRevenueSharePayable" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_oprx_IncreaseDecreaseInRevenueSharePayable" order="100" use="optional" weight="-1"/>
<loc xlink:type="locator" xlink:href="oprx-20171231.xsd#oprx_IncreaseDecreaseInRevenueSharePayableRelatedParty" xlink:label="loc_oprx_IncreaseDecreaseInRevenueSharePayableRelatedParty" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_oprx_IncreaseDecreaseInRevenueSharePayableRelatedParty" order="110" use="optional" weight="-1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_IncreaseDecreaseInAccruedLiabilities" xlink:label="loc_us-gaap_IncreaseDecreaseInAccruedLiabilities" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_us-gaap_IncreaseDecreaseInAccruedLiabilities" order="120" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_IncreaseDecreaseInDeferredRevenue" xlink:label="loc_us-gaap_IncreaseDecreaseInDeferredRevenue" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_us-gaap_IncreaseDecreaseInDeferredRevenue" order="130" use="optional" weight="1"/>
</calculationLink>
<calculationLink xlink:type="extended" xlink:role="http://OPRX/role/ConsolidatedStatementsOfCashFlow">
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_NetCashProvidedByUsedInInvestingActivities" xlink:label="loc_us-gaap_NetCashProvidedByUsedInInvestingActivities" />
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_PaymentsToAcquirePropertyPlantAndEquipment" xlink:label="loc_us-gaap_PaymentsToAcquirePropertyPlantAndEquipment" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInInvestingActivities" xlink:to="loc_us-gaap_PaymentsToAcquirePropertyPlantAndEquipment" order="10" use="optional" weight="-1"/>
<loc xlink:type="locator" xlink:href="oprx-20171231.xsd#oprx_PaymentsToAcquirePatientRights" xlink:label="loc_oprx_PaymentsToAcquirePatientRights" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInInvestingActivities" xlink:to="loc_oprx_PaymentsToAcquirePatientRights" order="20" use="optional" weight="-1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_PaymentsToAcquireIntangibleAssets" xlink:label="loc_us-gaap_PaymentsToAcquireIntangibleAssets" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInInvestingActivities" xlink:to="loc_us-gaap_PaymentsToAcquireIntangibleAssets" order="30" use="optional" weight="-1"/>
</calculationLink>
<calculationLink xlink:type="extended" xlink:role="http://OPRX/role/ConsolidatedStatementsOfCashFlow">
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:label="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities" />
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_ProceedsFromIssuanceOfCommonStock" xlink:label="loc_us-gaap_ProceedsFromIssuanceOfCommonStock" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="loc_us-gaap_ProceedsFromIssuanceOfCommonStock" order="10" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_PaymentsForRepurchaseOfCommonStock" xlink:label="loc_us-gaap_PaymentsForRepurchaseOfCommonStock" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="loc_us-gaap_PaymentsForRepurchaseOfCommonStock" order="20" use="optional" weight="-1"/>
</calculationLink>
<calculationLink xlink:type="extended" xlink:role="http://OPRX/role/ConsolidatedStatementsOfCashFlow">
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_CashAndCashEquivalentsPeriodIncreaseDecrease" xlink:label="loc_us-gaap_CashAndCashEquivalentsPeriodIncreaseDecrease" />
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:label="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_CashAndCashEquivalentsPeriodIncreaseDecrease" xlink:to="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" order="10" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_NetCashProvidedByUsedInInvestingActivities" xlink:label="loc_us-gaap_NetCashProvidedByUsedInInvestingActivities" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_CashAndCashEquivalentsPeriodIncreaseDecrease" xlink:to="loc_us-gaap_NetCashProvidedByUsedInInvestingActivities" order="20" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:label="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_CashAndCashEquivalentsPeriodIncreaseDecrease" xlink:to="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities" order="30" use="optional" weight="1"/>
</calculationLink>
<roleRef xlink:type="simple" xlink:href="oprx-20171231.xsd#PrepaidExpensesDetails" roleURI="http://OPRX/role/PrepaidExpensesDetails"/>
<calculationLink xlink:type="extended" xlink:role="http://OPRX/role/PrepaidExpensesDetails">
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_PrepaidExpenseCurrent" xlink:label="loc_us-gaap_PrepaidExpenseCurrent" />
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_PrepaidInsurance" xlink:label="loc_us-gaap_PrepaidInsurance" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_PrepaidExpenseCurrent" xlink:to="loc_us-gaap_PrepaidInsurance" order="10" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_PrepaidRent" xlink:label="loc_us-gaap_PrepaidRent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_PrepaidExpenseCurrent" xlink:to="loc_us-gaap_PrepaidRent" order="20" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="oprx-20171231.xsd#oprx_PrepaidExpensesFees" xlink:label="loc_oprx_PrepaidExpensesFees" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_PrepaidExpenseCurrent" xlink:to="loc_oprx_PrepaidExpensesFees" order="30" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="oprx-20171231.xsd#oprx_PrepaidLegalFees" xlink:label="loc_oprx_PrepaidLegalFees" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_PrepaidExpenseCurrent" xlink:to="loc_oprx_PrepaidLegalFees" order="40" use="optional" weight="1"/>
</calculationLink>
<roleRef xlink:type="simple" xlink:href="oprx-20171231.xsd#Patentandtrademarksdetails" roleURI="http://OPRX/role/Patentandtrademarksdetails"/>
<calculationLink xlink:type="extended" xlink:role="http://OPRX/role/Patentandtrademarksdetails">
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_FiniteLivedIntangibleAssetsGross" xlink:label="loc_us-gaap_FiniteLivedIntangibleAssetsGross" />
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_FiniteLivedIntangibleAssetOffMarketLeaseFavorableGross" xlink:label="loc_us-gaap_FiniteLivedIntangibleAssetOffMarketLeaseFavorableGross" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_FiniteLivedIntangibleAssetsGross" xlink:to="loc_us-gaap_FiniteLivedIntangibleAssetOffMarketLeaseFavorableGross" order="10" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_FiniteLivedPatentsGross" xlink:label="loc_us-gaap_FiniteLivedPatentsGross" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_FiniteLivedIntangibleAssetsGross" xlink:to="loc_us-gaap_FiniteLivedPatentsGross" order="20" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_OtherFiniteLivedIntangibleAssetsGross" xlink:label="loc_us-gaap_OtherFiniteLivedIntangibleAssetsGross" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_FiniteLivedIntangibleAssetsGross" xlink:to="loc_us-gaap_OtherFiniteLivedIntangibleAssetsGross" order="30" use="optional" weight="1"/>
</calculationLink>
<calculationLink xlink:type="extended" xlink:role="http://OPRX/role/Patentandtrademarksdetails">
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_FiniteLivedIntangibleAssetsNet" xlink:label="loc_us-gaap_FiniteLivedIntangibleAssetsNet" />
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_FiniteLivedIntangibleAssetsGross" xlink:label="loc_us-gaap_FiniteLivedIntangibleAssetsGross" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_FiniteLivedIntangibleAssetsNet" xlink:to="loc_us-gaap_FiniteLivedIntangibleAssetsGross" order="10" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_FiniteLivedIntangibleAssetsAccumulatedAmortization" xlink:label="loc_us-gaap_FiniteLivedIntangibleAssetsAccumulatedAmortization" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_FiniteLivedIntangibleAssetsNet" xlink:to="loc_us-gaap_FiniteLivedIntangibleAssetsAccumulatedAmortization" order="20" use="optional" weight="-1"/>
</calculationLink>
<roleRef xlink:type="simple" xlink:href="oprx-20171231.xsd#IncomeTaxesDetails" roleURI="http://OPRX/role/IncomeTaxesDetails"/>
<calculationLink xlink:type="extended" xlink:role="http://OPRX/role/IncomeTaxesDetails">
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_FederalIncomeTaxExpenseBenefitContinuingOperations" xlink:label="loc_us-gaap_FederalIncomeTaxExpenseBenefitContinuingOperations" />
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_CurrentFederalTaxExpenseBenefit" xlink:label="loc_us-gaap_CurrentFederalTaxExpenseBenefit" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_FederalIncomeTaxExpenseBenefitContinuingOperations" xlink:to="loc_us-gaap_CurrentFederalTaxExpenseBenefit" order="10" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="oprx-20171231.xsd#oprx_FederalIncomeTaxExpensesBenefitPermanentAndTimingDifferences" xlink:label="loc_oprx_FederalIncomeTaxExpensesBenefitPermanentAndTimingDifferences" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_FederalIncomeTaxExpenseBenefitContinuingOperations" xlink:to="loc_oprx_FederalIncomeTaxExpensesBenefitPermanentAndTimingDifferences" order="20" use="optional" weight="-1"/>
<loc xlink:type="locator" xlink:href="oprx-20171231.xsd#oprx_FederalTaxRateChange" xlink:label="loc_oprx_FederalTaxRateChange" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_FederalIncomeTaxExpenseBenefitContinuingOperations" xlink:to="loc_oprx_FederalTaxRateChange" order="30" use="optional" weight="-1"/>
<loc xlink:type="locator" xlink:href="oprx-20171231.xsd#oprx_FederalIncomeTaxExpensesBenefitValueAllowance" xlink:label="loc_oprx_FederalIncomeTaxExpensesBenefitValueAllowance" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_FederalIncomeTaxExpenseBenefitContinuingOperations" xlink:to="loc_oprx_FederalIncomeTaxExpensesBenefitValueAllowance" order="40" use="optional" weight="-1"/>
</calculationLink>
<roleRef xlink:type="simple" xlink:href="oprx-20171231.xsd#IncomeTaxesDetails1" roleURI="http://OPRX/role/IncomeTaxesDetails1"/>
<calculationLink xlink:type="extended" xlink:role="http://OPRX/role/IncomeTaxesDetails1">
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_DeferredTaxAssetsNet" xlink:label="loc_us-gaap_DeferredTaxAssetsNet" />
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_DeferredTaxAssetsOperatingLossCarryforwards" xlink:label="loc_us-gaap_DeferredTaxAssetsOperatingLossCarryforwards" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_DeferredTaxAssetsNet" xlink:to="loc_us-gaap_DeferredTaxAssetsOperatingLossCarryforwards" order="10" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="oprx-20171231.xsd#oprx_DeferredTaxAssetsTaxDeferredDepreciationAndAmortization" xlink:label="loc_oprx_DeferredTaxAssetsTaxDeferredDepreciationAndAmortization" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_DeferredTaxAssetsNet" xlink:to="loc_oprx_DeferredTaxAssetsTaxDeferredDepreciationAndAmortization" order="20" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_DeferredTaxAssetsTaxDeferredExpenseCompensationAndBenefitsShareBasedCompensationCost" xlink:label="loc_us-gaap_DeferredTaxAssetsTaxDeferredExpenseCompensationAndBenefitsShareBasedCompensationCost" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_DeferredTaxAssetsNet" xlink:to="loc_us-gaap_DeferredTaxAssetsTaxDeferredExpenseCompensationAndBenefitsShareBasedCompensationCost" order="30" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_DeferredTaxAssetsOther" xlink:label="loc_us-gaap_DeferredTaxAssetsOther" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_DeferredTaxAssetsNet" xlink:to="loc_us-gaap_DeferredTaxAssetsOther" order="40" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_DeferredTaxAssetsValuationAllowance" xlink:label="loc_us-gaap_DeferredTaxAssetsValuationAllowance" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_DeferredTaxAssetsNet" xlink:to="loc_us-gaap_DeferredTaxAssetsValuationAllowance" order="50" use="optional" weight="-1"/>
</calculationLink>
<roleRef xlink:type="simple" xlink:href="oprx-20171231.xsd#CommitmentsAndContingentLiabilitiesdetails" roleURI="http://OPRX/role/CommitmentsAndContingentLiabilitiesdetails"/>
<calculationLink xlink:type="extended" xlink:role="http://OPRX/role/CommitmentsAndContingentLiabilitiesdetails">
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_OperatingLeasesFutureMinimumPaymentsDue" xlink:label="loc_us-gaap_OperatingLeasesFutureMinimumPaymentsDue" />
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_OperatingLeasesFutureMinimumPaymentsDueCurrent" xlink:label="loc_us-gaap_OperatingLeasesFutureMinimumPaymentsDueCurrent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_OperatingLeasesFutureMinimumPaymentsDue" xlink:to="loc_us-gaap_OperatingLeasesFutureMinimumPaymentsDueCurrent" order="10" use="optional" weight="1"/>
<loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2017/elts/us-gaap-2017-01-31.xsd#us-gaap_OperatingLeasesFutureMinimumPaymentsDueInTwoYears" xlink:label="loc_us-gaap_OperatingLeasesFutureMinimumPaymentsDueInTwoYears" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_OperatingLeasesFutureMinimumPaymentsDue" xlink:to="loc_us-gaap_OperatingLeasesFutureMinimumPaymentsDueInTwoYears" order="20" use="optional" weight="1"/>
</calculationLink>
</linkbase>
