Relatively little is known about factors that initiate immunosuppression in tumors and act at the interface between tumor cells and host cells. In this article, we report novel immunosuppressive properties of the ribosomal protein S19 (RPS19), which is upregulated in human breast and ovarian cancer cells and released from apoptotic tumor cells, whereupon it interacts with the complement C5a receptor 1 expressed on tumor infiltrating myeloid-derived suppressor cells. This interaction promotes tumor growth by facilitating recruitment of these cells to tumors. RPS19 also induces the production of immunosuppressive cytokines, including TGF-β, by myeloid-derived suppressor cells in tumor-draining lymph nodes, leading to T cell responses skewed toward Th2 phenotypes. RPS19 promotes generation of regulatory T cells while reducing infiltration of CD8 T cells into tumors. Reducing RPS19 in tumor cells or blocking the C5a receptor 1-RPS19 interaction decreases RPS19-mediated immunosuppression, impairs tumor growth, and delays the development of tumors in a transgenic model of breast cancer. This work provides initial preclinical evidence for targeting RPS19 for anticancer therapy enhancing antitumor T cell responses.