Background Being an inevitable component of free tissue transfer, ischemia-reperfusion injury tends to contribute to flap failure. TNF- is an important proinflammatory cytokine and a prominent mediator of the ischemia-reperfusion injury. Etanercept, a soluble TNF- binding protein, has shown anti-inflammatory and anti-apoptotic effects in animal models of renal and myocardial ischemia-reperfusion injury. We have designed an experimental study to investigate the effect of etanercept on myocutaneous ischemia-reperfusion injury on transverse rectus abdominis myocutaneous flap model in rats.Methods Twenty-four male Sprague-Dawley rats were divided into 3 groups: In group 1 (sham), the TRAM flap was raised and sutured back without further intervention. In group 2 (control), the flap was raised and the ischemia-reperfusion protocol was followed. In group 3, etanercept (10 mg/kg, i.v.) was administered 10 minutes before reperfusion. At the end of the reperfusion period, biochemical and histolopathological evaluations were performed on serum and tissue samples.Results In the etanercept group the IMA and 8-OHdG levels (p=0.005 and p=0.004, respectively) were found significantly lower, and the GSH and SOD levels (p=0.01 and p<0.001, respectively) significantly higher in comparison to the control group. The histopathological analysis has revealed a lower degree of hyalinization, degenerated muscle fibers and nuclear change in the etanercept group compared to the control group.Conclusion The results of our experimental study indicate that etanercept offers protection against ischemia-reperfusion injury in skeletal muscle tissue, enhancing the TRAM flap viability. The ability of etanercept to induce ischemic tolerance suggests that it may be applicable in free-flap surgery.