Progressive multifocal leukoencephalopathy (PML) due to JC virus can be the initial manifestation of AIDS. A 40-year-old man seropositive for HIV-1 presented with aphasia, hemiparesis, and hemianopsia, and with magnetic resonance imaging of the brain typical of PML. He quickly became bed bound, incontinent, and mute. The diagnosis of PML was established by histopathology in a brain biopsy with positive immunocytochemistry for polyomavirus capsid proteins, and detection of JCV DNA by polymerase chain reaction using JCV-specific primers. High dose zidovudine therapy was initiated (1200 mg/day). Within two weeks the patient began to respond, and after three months he was able to walk and care for himself and was discharged. He lived for two years from the onset of PML. While cytarabine has been the drug most widely used for PML treatment, this is the second confirmed case with apparent response to zidovudine. High dose zidovudine may benefit some previously untreated AIDS patients with onset as PML.