Tramadolandalcoholareamongcommonlyabuseddrugs.Althoughtherearepo tentialdangersreportedupontheirmixing,therearenopreviousreportsdescribing thismixture'seffectsonthecardiovascularsystem(CVS).Theaimwastostudythe effectsofmixedalcoholandtramadolontheCVSofadultmalerats.Fiftyratswere divided into four groups: control, tramadol‐treated group, alcohol‐treated, and coadministrationgroups.Tramadolcausedasignificantincreasesincreatinekinase MB, troponinI,malondialdehyde, proteincarbonyl, 8‐hydroxy‐2′‐deoxyguanosine, andasignificantdecreaseintotalantioxidantcapacitywithhistologicalalterations insectionsoftheheartandaortaandasignificantincreaseinthearea%ofcollagen fiberswhile therewasanonsignificantdifference inbodyweight, heartweight, heartweight/bodyweight ratio, lipidprofile, tissue tumornecrosis factor‐αand interferon‐γ, intermediatemicrofilament proteins (IFPs) {desmin, vimentin, con nexin43}geneexpression,meanarea%ofelasticfibers inaortictissueandosteo pontinexpressionincardiacandaortictissue.Alcoholtreatmentcausedasignificant changeinall themeasuredparametersandmoredamageinhistological sections. Thechangeswerehighest inthecoadministrationgroup.Therewasastrongposi tivecorrelationbetweenthearea%ofcollagenfibersandvimentingeneexpression, andthearea%ofosteopontinexpressionwaspositivelycorrelatedtoconnexin43in cardiacandvasculartissue.Tramadol causesCVSinjurymainlythroughoxidative stresses, while thealcohol effect ismultifactorial;mixingbothaggravatesCVS injury. The studyalsohighlights the roleof IFPs andosteopontin‐expression in inducinginjury