A prolonged preoperative ischemic interval decreases the chances for successful replantation of an amputated limb. Skeletal muscle is especially sensitive to periods of prolonged ischemia. It is now hypothesized that significant tissue injury occurs during reperfusion, when oxygen-rich blood contacts anaerobic metabolites forming toxic oxygen free radicals. A replantation model, using the rabbit hind limb tibialis anterior muscle, was developed to assess muscle function and histological appearance following ischemic intervals of five and eight hours. Muscle strength five weeks after injury was used as a functional measurement of tissue damage. The effects of the superoxide free radical scavenger superoxide dismutase (SOD) and the hydroxyl radical scavenger dimethylsulfoxide (DMSO), administered systemically just before reperfusion, were studied. Muscle treated with SOD following five hours of ischemia had essentially normal strength and histological appearance; however, there was no protective effect after eight hours. DMSO treatment had no beneficial effects after five hours of ischemia, but after eight hours DMSO-treated muscle had significantly better function than untreated muscle. Histological examination confirmed the functional results. Clinical treatment of ischemic limbs with free radical scavengers before revascularization may aid in avoiding reperfusion injury and may improve survival and later muscle function.