<?xml version="1.0" encoding="US-ASCII"?>
<!-- Generated by Broadridge Transform (tm) - http://www.broadridge.com -->
<!-- Created: Wed Apr 29 19:53:45 UTC 2026 -->
<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-20260430.xsd#oprx_r_AdditionalDimensions" roleURI="http://www.optimizerx.com/role/AdditionalDimensions"/>
  <roleRef xlink:type="simple" xlink:href="https://xbrl.sec.gov/ecd/2025/ecd-2025.xsd#IndividualsOnly" roleURI="http://xbrl.sec.gov/ecd/role/IndividualsOnly"/>
  <roleRef xlink:type="simple" xlink:href="https://xbrl.sec.gov/ecd/2025/ecd-2025.xsd#PvpAdjustmentsOnly" roleURI="http://xbrl.sec.gov/ecd/role/PvpAdjustmentsOnly"/>
  <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:role="http://www.optimizerx.com/role/AdditionalDimensions" xlink:type="extended"/>
  <definitionLink xlink:role="http://xbrl.sec.gov/ecd/role/IndividualsOnly" xlink:type="extended">
    <loc xlink:type="locator" xlink:label="ecd_AllIndividualsMember" xlink:href="https://xbrl.sec.gov/ecd/2025/ecd-2025.xsd#ecd_AllIndividualsMember"/>
    <loc xlink:type="locator" xlink:label="oprx_WilliamFebboMember" xlink:href="oprx-20260430.xsd#oprx_WilliamFebboMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="ecd_AllIndividualsMember" xlink:to="oprx_WilliamFebboMember" order="2" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_StephenSilvestroMember" xlink:href="oprx-20260430.xsd#oprx_StephenSilvestroMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="ecd_AllIndividualsMember" xlink:to="oprx_StephenSilvestroMember" order="4" xbrldt:closed="true"/>
  </definitionLink>
  <definitionLink xlink:role="http://xbrl.sec.gov/ecd/role/PvpAdjustmentsOnly" xlink:type="extended">
    <loc xlink:type="locator" xlink:label="ecd_AllAdjToCompMember" xlink:href="https://xbrl.sec.gov/ecd/2025/ecd-2025.xsd#ecd_AllAdjToCompMember"/>
    <loc xlink:type="locator" xlink:label="oprx_LessReportedGrantDateValueOfEquityAwardsMember" xlink:href="oprx-20260430.xsd#oprx_LessReportedGrantDateValueOfEquityAwardsMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="ecd_AllAdjToCompMember" xlink:to="oprx_LessReportedGrantDateValueOfEquityAwardsMember" order="5" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_PlusMinusEquityAwardAdjustmentsMember" xlink:href="oprx-20260430.xsd#oprx_PlusMinusEquityAwardAdjustmentsMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="ecd_AllAdjToCompMember" xlink:to="oprx_PlusMinusEquityAwardAdjustmentsMember" order="7" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_PlusFairValueAtFiscalYearEndOfOutstandingAndUnvestedOptionAwardsAndStockAwardsGrantedInFiscalYearMember" xlink:href="oprx-20260430.xsd#oprx_PlusFairValueAtFiscalYearEndOfOutstandingAndUnvestedOptionAwardsAndStockAwardsGrantedInFiscalYearMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="ecd_AllAdjToCompMember" xlink:to="oprx_PlusFairValueAtFiscalYearEndOfOutstandingAndUnvestedOptionAwardsAndStockAwardsGrantedInFiscalYearMember" order="9" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_PlusChangeInFairValueOfOutstandingAndUnvestedOptionAwardsAndStockAwardsGrantedInPriorFiscalYearsMember" xlink:href="oprx-20260430.xsd#oprx_PlusChangeInFairValueOfOutstandingAndUnvestedOptionAwardsAndStockAwardsGrantedInPriorFiscalYearsMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="ecd_AllAdjToCompMember" xlink:to="oprx_PlusChangeInFairValueOfOutstandingAndUnvestedOptionAwardsAndStockAwardsGrantedInPriorFiscalYearsMember" order="11" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_PlusFairValueAtVestingOfOptionAwardsAndStockAwardsGrantedInFiscalYearThatVestedDuringFiscalYearMember" xlink:href="oprx-20260430.xsd#oprx_PlusFairValueAtVestingOfOptionAwardsAndStockAwardsGrantedInFiscalYearThatVestedDuringFiscalYearMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="ecd_AllAdjToCompMember" xlink:to="oprx_PlusFairValueAtVestingOfOptionAwardsAndStockAwardsGrantedInFiscalYearThatVestedDuringFiscalYearMember" order="13" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_PlusChangeInFairValueAsOfVestingDateOfOptionAwardsAndStockAwardsGrantedInPriorFiscalYearsForWhichApplicableVestingConditionsWereSatisfiedDuringFiscalYearMember" xlink:href="oprx-20260430.xsd#oprx_PlusChangeInFairValueAsOfVestingDateOfOptionAwardsAndStockAwardsGrantedInPriorFiscalYearsForWhichApplicableVestingConditionsWereSatisfiedDuringFiscalYearMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="ecd_AllAdjToCompMember" xlink:to="oprx_PlusChangeInFairValueAsOfVestingDateOfOptionAwardsAndStockAwardsGrantedInPriorFiscalYearsForWhichApplicableVestingConditionsWereSatisfiedDuringFiscalYearMember" order="15" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_LessFairValueAsOfPriorFiscalYearEndOfOptionAwardsAndStockAwardsGrantedInPriorFiscalYearsThatFailedToMeetApplicableVestingConditionsDuringFiscalYearMember" xlink:href="oprx-20260430.xsd#oprx_LessFairValueAsOfPriorFiscalYearEndOfOptionAwardsAndStockAwardsGrantedInPriorFiscalYearsThatFailedToMeetApplicableVestingConditionsDuringFiscalYearMember"/>
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="ecd_AllAdjToCompMember" xlink:to="oprx_LessFairValueAsOfPriorFiscalYearEndOfOptionAwardsAndStockAwardsGrantedInPriorFiscalYearsThatFailedToMeetApplicableVestingConditionsDuringFiscalYearMember" order="17" xbrldt:closed="true"/>
    <loc xlink:type="locator" xlink:label="oprx_TotalEquityAwardAdjustmentsMember" xlink:href="oprx-20260430.xsd#oprx_TotalEquityAwardAdjustmentsMember"/>
<!-- [WMV7][DP0IivIFYS1mFGZ2qwe7gGJFRQHQpy2lfw/UdmggioAbYnd5PCDA7bjbmv03oNCxo6rB1117cggo0jsqz5oVxtzF594uio+LoGLqSTV1XdihccFggPTr2i2ZP3QF6WK1CwTEQXqwcXalTj8IH+DwtdvxL+u1N9F059A74oquE7PjqzsMmWxWBde8PW0qjV0s7yUP86Wl/3td0R6XyPKbFAR5lVA0wTMz7hAAZngAuMDu5qfZ+mwPcMJFlL8MyzUbCrau22K62coiqS3SiXGf8xffK9+JkF6hS1eLn8TtW9KMmmD31IYNvQD1a7Nia6X2MmiiQB95ziaV1R5XYPmqcb6Nkh8jyA==] CSR-->
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="ecd_AllAdjToCompMember" xlink:to="oprx_TotalEquityAwardAdjustmentsMember" order="19" xbrldt:closed="true"/>
  </definitionLink>
</linkbase>
