A 39-year-old woman who had cryptogenic cirrhosis and who had received two liver transplants developed necrotic skin lesions over the chest, upper arms, and thighs. Biopsy showed enlarged endothelial cells with intranuclear and intracytoplasmic inclusions characteristic of cytomegalovirus (CMV) infection. However, a few multi-nucleated gaint cells were observed beneath a necrotic epidermis. This, combined with the clinical presentation, suggested to infectious disease consultants an infection with herpes simplex virus. Using the immunoperoxidase technique, inclusions stained positively with antibody to CMV and showed a negative reaction for herpes simplex antigen. In situ hybridization using biotinylated DNA probes on formalin-fixed, paraffin-embedded tissue sections confirmed the diagnosis of CMV infection and failed to substantiate infection with herpes simplex virus. Subsequently, blood cultures became positive for CMV. The early recognition of CMV infection in the skin permitted institution of antiviral therapy with gancyclovir. Specific skin lesions of CMV infection are likely to be encountered with increasing frequency among immunosuppressed patients. Lesions may be vesicular, and epidermal multinucleated giant cells can occasionally be identified. In situ hybridization is a technique that is readily adaptable to surgical pathology laboratories and permits both a rapid, specific diagnosis and the early institution of appropriate therapy.