BACKGROUND: Although a range of cytomegalovirus (CMV)-induced cutaneous manifestations is described in AIDS patients, skin involvement in immunocompromised patients is rare, and intraneural CMV inclusions or CMV neuritis has not been documented in skin biopsies. METHODS AND RESULTS: Cutaneous biopsies of CMV lesions were collected prospectively for 12 months. The morphology, sites and symptomatology of the individual lesions, associated systemic illnesses, treatment schedules and disease outcome were recorded. A total of nine biopsies were obtained from three females who presented with extensive painful perineal ulceration and disseminated cutaneous ulcers, nodules and plaques. Clinically, herpes simplex virus (HSV) ulceration was diagnosed and treatment with acyclovir was initiated after biopsies from the natal cleft, perineum and neck were obtained. All were superficial and demonstrated HSV infection. Only the natal cleft biopsy demonstrated coexistent CMV inclusions. Suboptimal healing necessitated two further biopsies from each patient, none of which demonstrated HSV inclusions. Three of four deep perineal biopsies demonstrated CMV inclusions within nerves attended by a lymphocytic infiltrate and architectural disturbances. Two deep cutaneous biopsies of the trunk and abdominal wall confirmed CMV in extraneural locations only. One superficial perineal biopsy did not demonstrate any viral inclusion. CONCLUSIONS: In documenting CMV neuritis in painful perineal ulcers, the histopathological spectrum of perineal CMV ulcers is expanded, a cutaneous neurotropic characteristic of CMV is presented and a direct role for CMV in the pathogenesis of pain is suggested. CMV latency within perineal nerves is also revisited as another potential site of CMV reactivation in immunocompromised patients, and another potential site for possible venereal transmission of CMV infection. The exclusive presence of HSV in initial superficial biopsies highlights the need for optimally biopsied tissue to confirm the coexistence of CMV infection.