Ischemia-reperfusion (I/R) injury caused by abrupt restoration of the circulation after prolonged ischemic insult induces significant morbidity after reconstructive microsurgery. The authors investigated whether a postconditioning (post-con) procedure attenuated skeletal muscle I/R injury and protected muscular function. Three hours of complete ischemia was induced by occluding the muscular branches of rat extensor digitorum longus (EDL) muscle. The post-con procedure was started at the end of ischemia and involved six cycles of 15 seconds of reperfusion followed by 15 seconds of re-occlusion (3 minutes of total intervention) prior to initiating unlimited reperfusion. EDL muscle contractilities were compared with those of normal sides (no ischemic exposure), and experimental group results were also compared with control group results (3 hours of ischemia followed by full reperfusion without post-con) at 3 hours and 5 days postreperfusion. Muscle wet weights, myeloperoxidase (MPO) activities, and histological results were also evaluated. The muscle contractilities in the post-con group were significantly preserved at both 3 hours and 5 days postreperfusion as compared with ischemic controls. Decreased inflammatory cell infiltration, MPO activity, and wet weight of postconditioned EDL muscle suggested that post-con attenuated acute inflammatory reactions induced by I/R. This study demonstrates that post-con provides effective functional protection to skeletal muscles from I/R injury.