Central nervous system disease has emerged as an important manifestation of acquired immunodeficiency syndrome in both the adult and pediatric populations, with neurologic abnormalities occurring in up to 90% of pediatric patients in some series. Neuropathologic studies, based primarily on the autopsy, have provided valuable insights into the spectrum and pathogenesis of acquired immunodeficiency syndrome-associated neurologic disorders, including primary human immunodeficiency virus encephalopathy and as the spectrum of infectious, neoplastic, and cerebrovascular diseases that may complicate the course of acquired immunodeficiency syndrome. Progressive encephalopathy represents the single most common neurologic disorder in pediatric acquired immunodeficiency syndrome and appears to be caused in most cases by direct infection in brain parenchyma by human immunodeficiency virus. Central nervous system lymphoma and cerebrovascular disease continue to account for most focal central nervous system lesions in the pediatric population. In contrast to adults with acquired immunodeficiency syndrome, opportunistic central nervous system infections remain relatively uncommon in the pediatric population. Our understanding of acquired immunodeficiency syndrome-associated neurologic disease remains far from complete. A plea is made for regular postmortem examination of the central nervous system in all patients dying with human immunodeficiency virus infection.