We report a case of a virulent, atypical herpes simplex infection in the brainstem of a patient with Acquired Immune Deficiency Syndrome (AIDS) which was characterized by demyelination and oligodendroglial tropism. At autopsy the brainstem showed demyelination. Immunocytochemistry, in situ hybridization, and electron microscopy confirmed the presence of herpes simplex virus (HSV). Viral cultures demonstrated HSV type 1. Neuroinvasiveness and neurovirulence were studied by intraperitoneal inoculation of susceptible mouse strains (A/J and Balb/cByJ) with different viral titers. The LD50 of the clinical isolate was 5 orders of magnitude greater than the LD50 of a laboratory HSV strain (HSV type 1 KOS). The brains of the mice inoculated with the clinical isolate showed brainstem and cerebellar demyelination.