Reperfusion injury is propagated by an inflammatory-mediated tissue edema and damage after reestablishment of vascular flow following an initial ischemic insult. In the field of transplantation, cyclosporin A(CsA) provides protection against chronic graft rejection through lymphocyte immunosuppression. Evidence for an independent protective effect of CsA against ischemia-reperfusion (IR) injury during organ transfer has prompted studies showing the benefit of CsA in various ischemia-exposed visceral organs. The authors hypothesized that CsA administration may similarly benefit IR injury after skeletal muscle amputations. To determine the effects of CsA on IR injury the authors induced 4 hours of ischemia on the gracilis muscle in a rat model. CsA (15 mg per kilogram orally) was administered in two experimental groups: (1) preischemic (N = 6): 48, 24, and 3 hours before ischemia; and (2) postischemic (N = 6): 30 minutes after induction of ischemia. The effects of CsA on IR muscle injury were observed in each of the experimental groups as well as a control group (N = 6) exposed to similar ischemia and administered a saline vehicle. Muscle viability (nitro blue tetrazolium staining) and muscle edema (wet-to-dry weight ratio) were assessed 24 hours after reperfusion. The preischemic CsA-treated gracilis muscle group demonstrated improved muscle viability (39.1 ± 4.8%) when compared with the ischemic control muscle group (23.8 ± 7.1%;p = 0.039). Furthermore, the preischemic CsA-treated muscle group demonstrated decreased edema (1.137 ± 0.095 times the contralateral nonischemic muscle) when compared with the control ischemic muscle group (1.248 ± 0.045 times the contralateral nonischemic muscle;p = 0.011). Although a trend toward improved muscle viability (32.1 ± 4.2%) and decreased edema formation (1.200 ± 0.062 times the contralateral nonischemic muscle) was observed in the peri-ischemic CsA-treated group when compared with the control ischemic muscle group, these differences were not significant. These observations confirm the beneficial effects of preischemic CsA therapy observed in organ transplantation research and suggest limited clinical use of peri-ischemic CsA therapy for patients with musculoskeletal amputations.