Introduction. Much of our knowledge regarding composite tissue allografts (CTAs) is derived from research in animal limb transplant models. We have demonstrated that CTAs like the rat hind limb consist of multiple tissues, some of which (skin, muscle) are highly immunogenic and trigger rapid rejection and others (lymph nodes and bone marrow) can initiate graft-versus-host disease (GVHD) in the host. The highly successful results of the initial trial of human hand transplantation have allowed us to differentiate rejection and GVHD in transplanted hands both clinically and by histopathology. In this study, we compare clinical signs and skin biopsies from the two Louisville recipients (at three and one year post-transplantation respectively), with those from patients with GVHD following bone marrow allotransplantation. The aim was to determine if the clinical or histopathologic changes of rejection were similar to those of GVHD. Results. Clinically, early rejection manifested as diffuse or patchy erythema localized to the allograft in both patients. Episodes of mild acute rejection resolved promptly and completely with topical medications, without the need to increase systemic immunosuppression. No clinical evidence of GVHD was observed in both our patients. Biopsies were taken from the site of intense dermatoerythema during episodes of acute rejection and from the distal forearm during the rejection-free period. Clinically evident rejection was associated with a perivascular and periadnexal lymphocytic infiltrate in the superficial dermis. This was associated with relatively little exocytosis of lymphocytes. There was no dyskeratosis of epidermis or hair follicle epithelium, and no apoptosis of keratinocytes. A few biopsies showed non-leucocytoclastic vasculitic changes in the small dermal arterioles with some destruction of basal epidermis. Some biopsies obtained more than two years after surgery showed epidermal atrophy with collagen sclerosis in the superficial dermis. Conclusions. Taken together, these findings at this early stage indicate that rejection in CTAs like hand transplants is directed more at small vessels than at epithelial structures (epidermis and adnexa). In comparison, GVHD in bone marrow transplant patients is associated with lesser lymphocytic infiltration in this distribution and greater direct involvement of the overlying epidermis. To date, there have been no reports of acute GVHD in any of the hand transplants performed around the world. Further follow-up of hand transplants by clinical, histopathologic and immunohistochemical studies will enable us to establish criteria for assessment of acute and chronic rejection or GVHD in clinical CTAs like hand transplants.