Exogenously administered mesenchymal stem/stromal cells (MSCs) suppress autoimmunity despite transient engraftment. However, the mechanism is unclear. In this study, we report a novel mechanism by which MSCs modulate the immune system by recruiting myeloid-derived suppressor cells in a mouse model of experimental autoimmune uveitis (EAU). Intravenous infusion of MSCs blocked EAU development and reduced Th1 and TH17 responses. Time course analysis revealed an increase of MHC class IIlo Ly6G-Ly6ChiCD11b+ cells in draining lymph nodes by MSCs. These Ly6ChiCD11b+ cells suppressed CD4+ cell proliferation and Th1/TH17 differentiation and induced CD4+ cell apoptosis. Adoptive transfer of Ly6ChiCD11b+ cells ameliorated EAU, whereas depletion of Ly6ChiCD11b+ cells abrogated the effects of MSCs. 1.8% of MSCs were present in draining lymph nodes 1 d after infusion, and MSCs with CCL2 knockdown did not increase MHC class IIloLy6G-Ly6ChiCD11b+ cells and failed to attenuate EAU. Therefore, our findings demonstrate that MSCs suppress autoimmunity by recruiting myeloid-derived suppressor cells into sites of inflammation in a CCL2-dependent manner.