There are two components to the reperfusion syndrome, which follows extremity ischemia. The local response, which follows reperfusion, consists of limb swelling with its potential for aggravating tissue injury and the systemic response, which results in multiple organ failure and death. It is apparent that skeletal muscle is the predominant tissue in the limb but also the tissue that is most vulnerable to ischemia. Physiological and anatomical studies show that irreversible muscle cell damage starts after 3 h of ischemia and is nearly complete at 6 h. These muscle changes are paralleled by progressive microvascular damage. Microvascular changes appear to follow rather than precede skeletal muscle damage as the tolerance of capillaries to ischemia vary with the tissue being reperfused. The more severe the cellular damage the greater the microvascular changes and with death of tissue microvascular flow ceases within a few hours-the no reflow phenomenon. At this point tissue swelling ceases. The inflammatory responses following reperfusion varies greatly. When muscle tissue death is uniform, as would follow tourniquet ischemia or limb replantation, little inflammatory response results. In most instances of reperfusion, which follows thrombotic or embolic occlusion, there will be a variable degree of ischemic damage in the zone where collateral blood flow is possible. The extent of this region will determine the magnitude of the inflammatory response, whether local or systemic. Only in this region will therapy be of any benefit, whether fasciotomy to prevent pressure occlusion of the microcirculation, or anticoagulation to prevent further microvascular thrombosis. Since many of the inflammatory mediators are generated by the act of clotting, anticoagulation will have additional benefit by decreasing the inflammatory response. In instances in which the process involves the bulk of the lower extremity, amputation rather than attempts at revascularization may be the most prudent course to prevent the toxic product in the ischemic limb from entering the systemic circulation.