Neuropathological examination of brain tissue of 100 patients with infection by the human immunodeficiency virus (HIV), including 98 with clinically manifest acquired immune deficiency syndrome (AIDS), revealed distinct multifocal-disseminated and diffuse brain tissue lesions, which can be regarded as HIV-induced brain lesions: multifocal giant cell encephalitis (MGCE; 4) and progressive diffuse leukoencephalopathy (PDL; 25). These lesions were found in 38 brains, and in 17 in absence of infectious, necrotizing or inflammatory changes of other types. In 13 brains, a combination of MGCE with PDL was seen, suggesting a spectrum of HIV-induced brain lesions. MGCE is characterized by perivascular accumulations predominantly of rod cells, monohistiocytes and macrophages, all of which are strongly labeled with a monoclonal antibody to macrophages. Most conspicuous are multinucleated giant cells which are also labeled by anti-macrophage antibody, and which can be regarded as evidence of the local presence of HIV, as confirmed by electron microscopical detection of HIV particles in four MGCE brains, and by immunocytochemical detection of HIV proteins in two MGCE brains. PDL is characterized by a triad: diffuse myelin loss, astroglial proliferation, and infiltration by mono- and multinucleated macrophages. HIV-induced lesions can be morphologically differentiated from histopathological brain lesions known in immunosuppression, including what is called here nodular encephalitis ["subacute encephalitis" of the literature, in most cases attributable to cytomegalovirus (CMV) or toxoplasmosis], by their characteristic histopathology including the hallmark presence of multinucleated giant cells, by direct immunocytochemical and electron microscopical demonstration of HIV in the lesions, and by the absence of opportunistic agents (bacteria, fungi, Toxoplasma, CMV, HSV or papovaviruses). Diffuse poliodystrophy (diffuse proliferation of astroglia with swollen nuclei, occasionally minor neuronal loss and rod cell proliferation) was found in the cerebral cortex and other gray matter in half of all brains, including cases with gyral atrophy, and may be another correlate of HIV damage to the brain. Morphological delineation of HIV-induced brain lesions is a necessary prerequisite for a meaningful clinical definition of HIV-induced cerebral disease.