THE depletion of CD4(+) T cells in AIDS is correlated with high turnover of the human immunodeficiency virus HIV-1(1,2) acid associated with apoptosis(3-5). The molecular mechanism of apoptosis in HIV infection, however, is largely unknown, T-cell apoptosis might be affected by viral proteins such as HIV-1 Tat(6-9) and gp120 (refs 10, 11). T-cell-receptor (TCR)-induced apoptosis was recently shown to involve the CD95 (APO-1/Fas) receptor(12). We show here that HIV-1 Tat strongly sensitizes TCR- and CD4(gp120)-induced apoptosis by upregulation of CD95 ligand expression. Concentrations of Tat found to be effective in cultures of HIV-1-infected cells were also observed in sera from HIV-1-infected individuals. Taken together, our results indicate that HIV-1 Tat and gp120 accelerate CD95-mediated, activation-induced T-cell apoptosis, a mechanism that may contribute to CD4(+) T-cell depletion(5,13,14) in AIDS.