Nuclear factor of kappa B (NF-kappaB) transcription factors are critical regulators of T-cell activation and survival. The relative contribution of individual NF-kappaB members to these processes remains elusive. We investigated the role of RelA in the regulation of CD8 T-cell activation. We overexpressed, in mature CD8 T cells, a transactivation domain-deficient RelA molecule (p65TAD). We show that p65TAD forms homo- and heterodimers with p50 that bind kappaB sites and selectively inhibit RelA-dependent transactivation. Expression of p65TAD does not affect initial activation or cell cycle progression but induces the death of activated CD8 T cells in vitro and in vivo. However, the long-term survival of resting effector CD8 T cells seems not to be affected by p65TAD expression. Collectively, our results indicate that RelA is a critical regulator of survival of proliferating CD8 T cells but may be dispensable for the survival of resting effector T cells.