Collaborative action between tumor cells and host-derived suppressor cells leads to peripheral tolerance of T cells to tumor antigens. Here, we showed that in tumor-bearing mice, generation of tumor antigen-specific effector T-helper cells (T_H1) was significantly attenuated, and impaired T_H1 differentiation was restored by the temporal blockade of interleukin (IL)-6 activity at the T-cell priming phase. Furthermore, we found that Gr-1⁺ myeloid-derived suppressor cells (MDSC) served as a source of IL-6 in tumor-bearing mice. Adoptive transfer of effector CD4⁺ T cells revealed that MDSC-sensitized effector CD4⁺ T cells were less potent in mounting antitumor immune responses, although effector T cells generated together with Gr-1⁺ cells from tumor-free mice eradicated established tumors. CD8⁺ T cells, IFN-γ, and MHC-class II expression in host mice were indispensable for the antitumor activity initiated by effector CD4⁺ T cells. Despite comparable suppressive activity of IL-6^+/+ and IL-6^−/− MDSC on primary T-cell activation, transfer of IL-6^+/+ MDSC, but not IL-6^−/− MDSC, dampened the efficient induction of effector T_H1 cells and counteracted CD4⁺ T cell–mediated antitumor immunity including cognate help for CD8⁺ T cells in vivo. These findings suggest that, apart from the inhibitory effects on primary T-cell activation, MDSC promote tumor progression by attenuating functional differentiation of tumor-specific CD4⁺ T cells into effector T_H1 cells through IL-6 production to promote tumor progression. This novel mode of MDSC-induced tolerance of effector CD4⁺ T cells should be considered as the basis for the rational design of effective T cell–mediated antitumor therapies. Cancer Immunol Res; 1(1); 64–76. ©2013 AACR.