Lack of antitumor immunity is often related to impaired CD8 T-cell responses that could result from a poor priming capacity by tumor-infiltrating dendritic cells (TIDC) and/or further inhibition by regulatory T cells (T_reg). Interleukin-10 (IL-10) has been implicated in the inhibition of TIDC as well as in the generation and functions of T_reg. Here, we address some of the respective and possibly overlapping roles of IL-10 and CD25⁺ T_reg in CD8 antitumor immunity. Whereas tumor antigen–specific CD8 T cells proliferated in vivo in the presence of IL-10 or T_reg, optimal effector functions were observed in mice lacking both IL-10 and T_reg. Indeed, tumors grown in normal but not in IL-10–deficient or CD25-depleted mice induced tumor antigen–specific CD8 suppressor T cells. Suppression involved transforming growth factor-β. Similarly, both IL-10 and T_reg were responsible for impaired CD8 T cell priming by TIDCs, but IL-12 production by TIDCs was prevented only by T_reg-independent IL-10. Subsequently, IL-10 defect and T_reg depletion were required to achieve optimal induction of CD8 T-cell effectors by TIDC following CpG activation. Our results point out major redundant and nonredundant roles for IL-10 and T_reg in the inhibition of TIDC-mediated generation of antitumor CD8 T-cell response.