Interleukin-10 (IL-10) is a potent anti-inflammatory cytokine that regulates immune responses. IL-10 has also been shown to enhance antitumor CD8⁺ T-cell responses in tumor models although the underlying mechanisms are not fully understood. In this study, we used a series of genetic mouse models and the mouse plasmacytoma J558 model to investigate this issue. J558 tumors grew significantly faster in IL-10^−/− mice than in wild type (WT) mice, but similarly in IL-10^−/−Rag2^−/− and Rag2^−/− mice. Tumors from IL-10^−/− mice contained fewer IFN-γ-producing CD8⁺ and CD4⁺ T cells than tumors from WT mice. Strikingly, depletion of total CD4⁺ T cells, but not CD25⁺ cells, resulted in tumor eradication in IL-10^−/− mice. Adoptive transfer studies revealed that CD4⁺ T cells from IL-10^−/− mice exhibited more potent suppression of cytotoxic T lymphocyte (CTL)-mediated tumor rejection than their WT counterparts, and IL-10–deficient tumor-infiltrating CD4⁺ T cells expressed higher levels of PD-L1 and CTLA-4 inhibitory molecules. Although IL-10–deficient CD8⁺ T cells are not defective in activation and initial rejection of tumors, adoptive transfer studies using IL-10–deficient P1CTL transgenic T cells that recognize the tumor rejection antigen P1A reveal that IL-10 is required for long-term persistence of CTLs and control of tumor growth. Thus, we have found that IL-10 enhances antitumor CTL responses by inhibiting highly suppressive CD4⁺ T cells and promoting CTL persistence. These data have important implications for the design of immunotherapy for human cancer.