Although CD8+ T cells play a central role as immune effectors, CD4+ T cells act to control the activation and persistence of the CD8+ T cell response in autoimmune disease, antiviral immunity, and experimental systems with immunogenic model tumor Ag. However, little information is available on the effects of CD4+ T cells on the function of endogenous CD8+ T lymphocytes recognizing authentic tumor rejection Ag with limited immunogenicity. We report here that the prophylactic or postchallenge administration of T helper Th1-type and Th2-type CD4+ clones specific for an unmutated rejection Ag (murine P815AB, resembling tumor-specific shared Ag in humans) leads to the induction of P815AB-specific reactivity in vivo and concomitant tumor destruction, with quantitative rather than qualitative differences characterizing the antitumor activity of Th1 vs Th2 cells. Because the transferred CD4+ cells lacked direct antitumor activity in vitro and required the de novo generation of P815AB-specific CD8+ T cells in vivo, these findings suggest that CD4+ lymphocytes can enhance the ability of host APC to initiate an endogenous CD8+ T cell response to authentic, poorly immunogenic tumor rejection Ag.