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Background: Ischemia-reperfusion injury may lead to insufficient microcirculation and results in partial flap loss during the free flap surgeries., Objective: This study aimed to investigate the effect of trimetazidine (TMZ) on oxidative stress, inflammation and histopathological changes, using the epigastric skin flap model in rats., Methods: 40 male Wistar rats were used, that were divided into four groups. Control group, non-treated ischemic (I/R)-group and two trimetazidine treated groups (preischemically, postischemically) were established. To create ischemia in the skin flap, the superficial epigastric vessels were clamped for six hours, followed by twenty-four hours of reperfusion. Blood samples and biopsies from skin flaps were collected at the end of the reperfusion period. The inflammatory response, the degree of oxidative stress (by measuring the plasma level of malondialdehyde (MDA), reduced glutathione (GSH); sulfhydryl (-SH) groups) and histopathological changes were evaluated., Results: Inflammatory response, and oxidative stress were significantly attenuated in the trimetazidine treated groups, compared to the non-treated ischemic group. Histopathological findings were also correlated with the biochemical results., Conclusion: In our study trimetazidine could reduce the ischaemia-reperfusion injury, even after an unexpected ischemic period, so it is a promising drug during free tissue transfer, replantation or during revascularization procedures in the future.