Abstract Ag-specific CD8+ T cells immunized in the absence of CD4+ T cell help, so-called “unhelped” CD8+ T cells, are defective in function and survival. We investigated the role of the proapoptotic molecule TRAIL in this defect. We first demonstrate that TRAIL does not contribute to the CD8+ T cell response to Listeria monocytogenes strain expressing OVA (LmOVA) in the presence of CD4+ T cells. Secondly, we generated mice doubly deficient in CD4+ T cells and TRAIL and analyzed their CD8+ T cell response to LmOVA. Memory CD8+ T cells in double-deficient mice waned over time and were not protective against rechallenge, similar to their TRAIL-sufficient unhelped counterparts. To avoid the effects of CD4+ T cell deficiency during memory maintenance, and to address whether TRAIL plays a role in the early programming of the CD8+ T cell response, we performed experiments using heterologous prime and early boost immunizations. We did not observe activation-induced cell death of unhelped CD8+ T cells when mice were infected with followed vaccinia virus expressing OVA 9 days later by LmOVA infection. Furthermore, primary immunization of CD4+ T cell-deficient mice with cell-associated Ag followed by LmOVA infection did not reveal a role for TRAIL-mediated activation-induced cell death. Overall, our results suggest that CD4+ T cell help for the CD8+ T cell response is not contingent on the silencing of TRAIL expression and prevention of TRAIL-mediated apoptosis.