A certain subset of patients fails free tissue transfer regardless of technical factors. It is likely that flap ischemia and subsequent reperfusion is contributing to such failures. Furthermore, of those muscle flaps that ultimately survive after revision surgery, functional deficits exist that preclude effective function of the flap. Currently, there is no universally accepted modality for treatment or prevention of such free tissue failures. It has been shown that vasoactive mediators such as nitric oxide are involved in the period of ischemia/reperfusion and are likely initiators of a cascade of events that ultimately lead to late phase ischemia/reperfusion protection. Twenty-seven male Sprague-Dawley rats were used in 3 arms of the study involving isolation of the neurovascular pedicle and induction of ischemia in the extensor digitorum longus muscle. Experimental animals systemically received the nitric oxide donor spermine-NONOate before a six-hour “flap” ischemia period involving the extensor digitorum longus (EDL) muscle. Twenty-one days after the ischemic insult, the EDL muscle was analyzed by tetanic force testing, followed by histology. Sham and control animals underwent identical analysis. Data demonstrates functional benefits in tetanic force testing in animals treated with intravenous spermine-NONOate before muscle flap ischemia compared to sham animals (I/R L-R vs. I/R + Sper NONOate L-R, p<0.0001). Histology reveals attenuation in the stigmata of organ and cellular ischemic injury in the pre-treated group compared to the ischemia-only group in animals treated with Spermine NONOate 30 minutes before ischemic insult. Treatment with intravenous spermine-NONOate 30 minutes before prolonged ischemia of a skeletal muscle confers physiologic and histologic advantages 21 days after injury in a rat muscle flap model of prolonged ischemia.