Myeloid-derived suppressor cells (MDSCs) inhibit T-cell activity and promote tumor growth in tumor-bearing hosts. We sought to determine how to prevent the generation of these cells and modulate anti-tumor immunity at different times during tumor growth. Interleukin-4 (IL-4), a cytokine closely associated with the differentiation of myeloid cells, was expressed locally at the tumor site with its dose and expression time tightly regulated by a tet-off system. Early exposure of high-dose IL-4 to the tumor stromal cells effectively prevented the generation of myeloid suppressor cells and led to a T-cell-mediated tumor rejection. However, IL-4 had no effect a few days after tumor growth, when myeloid suppressor cells had been generated and T cells were tolerized. Importantly, coinoculation of IL-4 receptor (IL-4R)-deficient tumor cells with IL-4R competent, but not IL-4R-deficient myeloid cells led to IL-4-mediated tumor regression in IL-4R-deficient mice, indicating that IL-4 acts directly on myeloid cells. These results show a novel way to prevent T cells from MDSC-induced suppression, with important indications for cancer therapy.