Epidemiologic studies have identified cocaine as a cofactor for development of acquired immunodeficiency syndrome (AIDS). To evaluate this interaction, human peripheral blood leukocytes (PBL) were implanted into severe combined immunodeficient mice and infected with human immunodeficiency virus (HIV) in both the presence and absence of cocaine. Concurrent administration of cocaine resulted in significantly more PBL becoming infected with HIV in vivo (38.85% vs. 18.5%). The number of CD4(+) cells recovered from HIV-infected, cocaine-treated animals was significantly lower than that from mice infected with HIV in the absence of cocaine (6.5 x 10(4) vs. 19 x 10(4)) and was associated with a lower CD4:CD8 ratio and a dramatic increase in virus load. Exposure to cocaine alone did not affect the implantation of PBL, suggesting a specific interaction between cocaine and HIV. This report describes a model for evaluating HIV cofactors and supports cocaine's role in the development and progression of AIDS.