Morbidity and mortality after revascularization of acute ischemic limbs remain high, despite many surgical improvements during the last decades. To a large extent, this is related to reperfusion itself after complete, acute, prolonged ischemia that results in postreperfusion syndrome. This report addresses the deleterious consequences of postreperfusion syndrome, which occurs after normal blood reperfusion, and describes the pathophysiologic basis for this complication. A unique opportunity arises from these data. Control of the initial reperfusion by modifying the conditions of reperfusion and the composition of the reperfusate will open the door to a new approach to salvage limbs and lives from this disastrous complication. The same approach that is used successfully in other organs and tissues (eg, heart, kidney, brain, whole body) will put the vascular surgeon in the position to intraoperatively counteract the consequences of revascularization after prolonged acute limb ischemia.