Immunohistochemical localization of human immunodeficiency virus type 1. (HIV-1) in central nervous system lymphoma lesions and uninvolved regions of the brain in seven patients with AIDS revealed evidence of frequent association of HIV-labeled macrophages and multinucleated giant cells with the lesions. Five of seven cases displayed a higher density of labeled cells within and at the periphery of mass lesions and angiocentric infiltrates than in brain parenchyma farther than 1 cm from such lesions. In addition, no label was detected within the neoplastic lymphoid cells in any patient. HIV could not be localized within similarly appearing macrophages associated with destructive lesions (e.g. related to cytomegalovirus encephalitis) or small thrombotic infarcts in brain tissue from the same patients. All lymphomas studied were of a high-grade B-cell type with similar histology in multiple sites. Leptomeningeal spread of the tumor was found in all cases. Facilitation of the development of malignant B-cell clonal proliferation might occur in foci of HIV replication. Alternatively, the development of lymphoma may be due to the generalized immunosuppression; in this case, local activation of macrophages in proximity to the malignant lymphocytes might lead to preferential concentration of disseminated virus by these cells.