Background The first human hand allograft, performed in Lyon, France, on September 23, 1998, was removed during month 29 posttransplantation as the result of rejection because the patient did not comply with the immunosuppressive treatment. Methods The patient was regularly examined from the day of transplantation to amputation. Biopsies were taken from the skin of the allograft and examined immunohistologically. After amputation, various tissue specimens obtained from the allograft (including skin, tendons, bone, muscles, and joints) were studied. Results From month 15 onward, the allografted skin presented lichenoid papules that progressively spread and coalesced into diffuse erythematous-scaly lesions over the allografted hand. Histologically, these showed an aspect of chronic lichenoid cutaneous graft-versus-host disease. At the time of amputation, erosive and necrotic areas over the skin were present. Pathologic examination of the allograft showed that the most severe changes were found in the skin. Mild inflammation was found in muscles and tendons. Bones (including bone marrow) and joints were spared. Conclusions The skin is the main target of rejection in human hand allografts. Close clinicopathologic monitoring of the skin is the most reliable way to detect rejection in human composite tissue allografts.