Peripheral blood monocytes (PBM) can selectively lyse malignant or virus-infected cells. We investigated the effects of target cell infection with HIV-1 on PBM cytolytic function. Cytokine-activated PBM lysed uninfected, HSV-1-infected or vaccinia virus-infected tumor cells, but did not lyse the same cell lines when infected with the human immunodeficiency virus type 1 (HIV-1). HIV did not impair PBM viability, and actinomycin D (Act D) pretreatment of HIV-infected target cells restored their susceptibility to PBM-mediated lysis. Either antibody to CD4 (Leu3a) or a recombinant vaccinia virus that induces expression of the HIV envelope protein, also inhibited target cell lysis by PBM. These studies indicate that CD4 can function as a mediator of PBM cytolytic function, and that target cell expression of the HIV-1 envelope protein may inhibit monocyte-mediated antitumor responses.