Multinucleated giant cells (MGCs) were found in the brains of two patients with the acquired immune deficiency syndrome (AIDS), but were absent in five other AIDS brains. In one case there was a distinctive distribution of MGCs in disseminated clusters; damage of brain parenchyma was minor or absent. In another case, MGCs were restricted largely to the perivascular spaces and were accompanied by lesions of toxoplasmosis and cytomegalovirus infection. In paraffin sections, morphological and histochemical-staining characteristics of MGCs were similar to those of macrophages. Occasional immuno-labeling of MGCs with monoclonal antibody to leukocyte common antigen suggested a hematogenous origin. MGCs were not stained by immunocytochemistry for neural markers glial fibrillary acidic protein, S 100 protein, neurofilament proteins, neuron specific enolase, and myelin basic protein and, therefore, appear unlikely to originate from the neuroepithelium. In the absence of evidence of other infections in case 1, the peculiar tissue reaction found could be a direct result of infection by the AIDS retrovirus. The formation of MGCs is likely to represent a cytopathic effect of the virus on lymphoid or monohistiocytic cells infiltrating the brain (infection of these cells could occur before or after they entered the brain). These assumptions are supported by the finding of similar MGCs in permissive lymphoid cell cultures after infection with the AIDS retrovirus.