The effect of tumor necrosis factor (TNF) on the replication of human immunodeficiency virus type 1 (HIV-1) was investigated in several T4 lymphocyte cell lines. TNF markedly enhanced the cytopathogenicity of HIV-1, virion-associated reverse transcriptase (RT) activity in the cell culture supernatant, and viral antigen expression in MOLT-4 cells as early as 3 days after HIV-1 infection. A slight increase in RT activity was also observed in the supernatant of H9 cell cultures exposed to TNF. However, TNF did not increase either RT activity in MT-4 cell supernatants or viral antigen expression in HUT-78 cells. Thus, TNF is able to stimulate the replication of HIV-1 in de novo infected T4 cells although not all T4 cells seem to be sensitive to this stimulatory effect.