We have proposed that inappropriate induction of programmed cell death (PCD) or apoptosis, a physiological cell-suicide process, may play a role in the pathogenesis of AIDS. This model has been supported by several reports of abnormal levels of PCD in vitro in both CD4+ and CD8+ T cells from human immunodeficiency virus type 1 (HIV-1)-infected persons. To further assess the significance of such a process in AIDS pathogenesis, in vitro PCD was compared in HIV-1-infected persons and in various primate models that allow discrimination between pathogenic chronic lentiviral infection either in the same species, such as rhesus macaques infected with different simian immunodeficiency viruses (SIV), or in different species, such as SIV-infected African green monkeys and HIV-1-infected chimpanzees. Abnormal levels of PCD in CD4(+)-T-cell-depleted peripheral blood mononuclear cells (PBMC), containing the CD8+ T cells, were observed in both pathogenic and nonpathogenic models. However, abnormal levels of PCD in the CD8(+)-T-cell-depleted PBMC, containing the CD4+ T cells, was only observed in the two models leading to AIDS: HIV-1-infected persons and rhesus macaques infected with a pathogenic strain of SIV. This suggests that inappropriate T-cell PCD in HIV-1-infected persons involves two distinct processes: one, concerning CD4+ T cells, is closely related to AIDS pathogenesis; and the other, concerning CD8+ T cells, may be a consequence of immune stimulation with no direct link to AIDS pathogenesis.