Differential and sometimes contradictory effects have been described for tumour necrosis factor α (TNF-α) and interferon γ (IFN-γ) on replication of human immunodeficiency virus type 1 (HIV-1). The authors examined individual and co-ordinate action of these cytokines on HIV-1 expression, and on apoptosis of HIV-1-infected host cells by determination of reverse transcriptase activity in cell culture supernatant, expression of HIV-1-RNA and production of p24 antigen in the promonocytic cell line U937 and its persistently HIV-1-infected clone U1. Apoptosis was demonstrated by typical cleavage of cellular DNA at internucleosomal regions in promonocytic and T-lymphocytic cell lines. TNF-α alone markedly stimulated HIV-1 replication in U1 cells at the transcriptional and on the translational level. Exclusive application of IFN-γ only slightly enhanced HIV-1 expression, whereas it synergistically potentiated stimulatory effects of TNF-α. Both cytokines also synergistically induced apoptosis in HIV-1-infected host cells. Co-ordinate action of TNF-α and IFN-γ is suggested to represent an important mechanism for disease progression in HIV infection. These findings demonstrate that cytokine effects on viral expression may vary depending on their single or combined application.