Previous studies have shown that cocaine consumption alters the normal immune functions of animals. Several epidemiologic studies have indicated an association between cocaine consumption and an increased risk for AIDS. In the present studies, unstimulated peripheral blood mononuclear cells (PBMC) isolated from 8 healthy, human immunodeficiency virus (HIV) type 1-seronegative volunteers were exposed to cocaine or one of its by-products, in vitro, at concentrations compatible with blood levels found during clinical abuse of cocaine. PBMC treated with cocaine had significantly increased levels of HIV-1 replication after infection in vitro compared with untreated PBMC. The major cocaine by-product, benzoylecgonine, did not appear to exert any significant potentiating effect on HIV-1 replication. Cocaine or its by-product did not significantly increase HIV-1 replication in persistently HIV-1-infected T lymphocytic or monocytoid cell lines. These data indicate that exposure of PBMC but not chronically HIV-1-infected cell lines to cocaine can result in increased HIV-1 replication.