Aging is associated with a decrease in naïve (T(N)) and central memory (T(CM)), and an accumulation of effector memory (T(EM) and T(EMRA)) T cell subsets. Previously, we have demonstrated an increased sensitivity of T(N) and T(CM) CD4+ and CD8+ T cells in aging to TNF-alpha-induced apoptosis. In this investigation, we examined whether similar differential sensitivity is applicable to CD95-mediated apoptosis. We show that T(N) and T(CM) CD4+ and CD8+ T cells from aged subjects are significantly more sensitive to CD95-mediated apoptosis. Increased apoptosis is associated with increased activation of caspase-8 and caspase-3. Both caspase-8 and caspase-3 inhibitors blocked CD95-mediated apoptosis and activation of caspase-8 and caspase-3 in T(N) and T(CM) CD4+ and CD8+ T cells. No significant difference was observed in apoptosis or in activation of caspase-8 and caspase-3 in T(EM) and T(EMRA) CD4+ and CD8+ T cells between young and aged subjects; both populations were relatively and comparably resistant to CD95-mediated apoptosis and caspase activation. No correlation was observed between the sensitivity/resistance of any of the subsets of CD4+ or CD8+T cells to CD95-mediated apoptosis and the expression of CD95. Our data suggest that increased CD95-mediated apoptosis of T(N) and T(CM) CD8+ and CD4+ T cells may play a role in their decline in human aging.