This study analyzes the influence of all-trans retinoid acid (tRA) on apoptosis of peripheral lymphocytes from human immunodeficiency virus (HIV)-positive patients. tRA inhibits the ex vivo apoptosis in T cells; a more potent effect was observed on activation-induced apoptosis. Phenotypic characterization of T cell subsets prevented from anti-CD3-induced apoptosis by tRA revealed a more potent effect on CD4 T cells. A central regulatory system for apoptosis is the CD95 system, and inappropriate induction of this pathway is thought to contribute to AIDS pathogenesis. In investigation of CD95-based apoptosis, tRA had no effect on activation-dependent induction of CD95 on T lymphocytes, but it inhibited the induction of CD95 ligand expression on anti-CD3-activated T cells. The previously reported in vivo effect of tRA inhibiting HIV-associated apoptosis and the present observations suggest that tRA could be considered to down-regulate apoptosis associated with AIDS pathogenesis.