Vascularized first set human skin allografts were rejected largely by a process of extensive and progressive microvascular damage leading to ischemia and infarction. Microvascular injury was associated with a cellular immune response. However, vessel damage was at least in part immunologically nonspecific because vessels of the graft bed (host tissue) were damaged as well as those of the graft itself. We conclude that the microvascular endothelium is the critical target of the immune response in vacularized skin allografts in man, and that this sequence of events--primary vascular damage followed by ischemic infarction--may have significance in a variety of experimental and clinical settings.