Within a 5-month period, 2 homosexual men with persistent lymphadenopathy developed clinical findings consistent with herpes simplex virus (HSV) encephalitis. These signs included abrupt change in mental status, seizures, cerebrospinal fluid pleocytosis, and localized electroencephalographic abnormalities showing temporal lobe involvement. Initial computed tomographic scans were unremarkable. Treatment with adenine arabinoside was instituted and temporal lobe biopsies were performed. Although virus-specific antigens were detectable in only 1 patient, cultures of biopsy tissue from both patients yielded HSV type 2 organisms. Spiking fevers persisted and the patients failed to improve, prompting administration of acyclovir. Both patients recovered gradually after their second course of antiviral therapy and survived with severe neurological deficits. These patients should raise concerns about an increased incidence of type 2 encephalitic illness among homosexual men with persistent lymphadenopathy or acquired immune deficiency syndrome. In addition, the importance of using HSV type 2 antibody in the immunofluorescence test of brain biopsy tissue for rapid diagnosis of the disease is emphasized.