In this investigation, we have examined the relative sensitivity of human naïve, central memory (TCM), and two types of effector memory CD8+ T cells (TEM and TEMRA) to TNF-α-induced apoptosis. Our data show that naïve and TCM CD8+ T cells were sensitive, whereas TEM and TEMRA CD8+ T cells were relatively resistant to TNF-a-induced apoptosis. The apoptosis profile correlated with the activation of caspase-8 and caspase-3. However, no correlation was observed between relative sensitivity of four CD8+ T cell subsets to apoptosis and the expression of TNFR-I or TNFR-II. TEM and TEMRA CD8+ T cells displayed increased phosphorylation of IKKα/β and IκB and increased NF-κB activity as compared to naïve and TCM CD8+ T cells. Bcl-2, Bcl-xL and FLIPL expression was higher and Bax expression was lower in TEM and TEMRA CD8+ T cells as compared to naïve and TCM CD8+ T cells. These data suggest that signaling molecules downstream of TNFRs may be responsible for differential sensitivity among subsets of CD8+ T cells to TNF-α-induced apoptosis.