We describe a patient who presented with an acute monophasic illness characterized by behavioral abnormalities, visual illusions, and a seizure, who had magnetic resonance- and brain biopsy-documented evidence of multifocal central nervous system demyelination. Serological studies were diagnostic of recent Epstein-Barr virus infection and included evidence of intrathecal synthesis of Epstein-Barr virus-specific IgG antibodies against the viral capsid antigen. Viral DNA could not be amplified from cerebrospinal fluid by polymerase chain reaction, and viral antigen and genome were not detected in the brain biopsy specimen. The patient's clinical course, diagnostic studies, and neuropathological findings all support the diagnosis of a postinfectious Epstein-Barr virus-mediated demyelinating encephalopathy.