Apoptotic cell death plays a fundamental role in the maintenance of tissue homeostasis in complex biological systems. It is also a major mechanism for keeping immune reactions in check. Members of the TNF family of receptors and cytokines are implicated in the regulation of apoptotic signals that shape the immune system. In this study, we have examined the role of three members of the TNFR family, Fas (CD95), TNFR1 (p55), and TNFR2 (p75), in inducing cell death in Con A-activated CD4 and CD8 T cells. It was found that Con A-activated p55−/− CD4 or CD8 T cells were highly resistant to TNF-induced cell death. By contrast, although activated p75−/− CD4 or CD8 T cells were killed by TNF, they were more resistant to TNF-induced killing when compared with p75+/+ cells, particularly at higher concentrations of TNF. We also determined whether activated p55−/− and p75−/− T cells differ in their sensitivity to cell death induced by TCR cross-linking. We found that activated p55−/− CD4 or CD8 T cells were equally susceptible to TCR-induced cell death. More interestingly, the loss of the p75 receptor conferred resistance to TCR-induced death in activated CD8, but not CD4 T cells. This resistance to TCR-induced death in activated p75−/− CD8 T cells correlated with the resistance of these cells to Fas/Fas ligand-induced cell death.