It has been proposed that direct and indirect mechanisms contribute to the unresolved issue of CD4⁺ T-cell depletion that results from HIV-1 infection. We recently reported that plasma levels of tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) are elevated in HIV-1–infected patients and that they correlate with viral load. The present study investigates the expression of TRAIL death receptor 5 (DR5) in the peripheral-blood mononuclear cells (PBMCs) of HIV-1–infected patients and its role in CD4⁺ T-cell death. DR5 expression was elevated and associated with the apoptotic marker annexin V. Apoptosis was reduced in CD4⁺ T cells when cultured with anti-DR5 antibody. CD4⁺, but not CD8⁺, T cells from uninfected donors expressed TRAIL, DR5, and activated caspase-3 when cultured with infectious or noninfectious HIV-1, resulting in preferential apoptosis of CD4⁺ T cells. TRAIL, caspase-3 expression, and apoptosis were type 1 interferon (IFN) dependent. Induction of apoptosis and DR5 expression required glycoprotein 120 (gp120)–CD4 interaction. Finally, we analyzed DR5 expression by CD4⁺ T cells in highly active antiretroviral therapy (HAART)–treated patients. The decreased viral loads and increased CD4 counts of HAART-responsive patients were associated with a decrease in DR5 mRNA expression by CD4⁺ T lymphocytes. We propose a novel model in which a type 1 IFN–regulated TRAIL /DR5 mechanism induces apoptosis of HIV-1–exposed CD4⁺ T cells.