Delta-9-tetrahydrocannabinol (THC), the major psychoactive component in marijuana, and the murine retrovirus, Friend leukemia virus (FLV), have been demonstrated to depress cellular immune function, including lymphocyte blastogenic transformation and natural killer cell activity. The present study demonstrates tht the two agents can work in concert to depress these immune activities more severely than either agent administered by itself. When 7.5-10 micrograms/ml THC was added in vitro to spleen cells from mice infected 2-4 weeks earlier with FLV there was a noticeable decrease, beyond that seen with the drug or virus alone, for both lymphocyte blastogenesis and natural killer cell cytotoxicity. In addition, when both FLV and THC were administered to mice concurrently with infection by herpes simplex virus (HSV), mortality attributed to the retrovirus infection occurred significantly more rapidly than in the absence of the drug and HSV. The data indicate that THC acted in the presence of a HSV infection to enhance the FLV induced mortality. By extrapolation to the human condition, these results suggest that marijuana could serve as a cofactor, possibly in conjunction with opportunistic pathogens, in the progression of infection due to the human immunodeficiency virus from latency to overt acquired immunodeficiency syndrome.