Toxic shock syndrome (TSS) and other superantigen-mediated illnesses are associated with ‘systemic’ immunosuppression that jeopardizes the host's ability to fight pathogens. Here, we define a novel mechanism of ‘local’ immunosuppression that may benefit the host. Systemic exposure to staphylococcal enterotoxin B (SEB) rapidly and selectively recruited CD11b+Gr-1highLy-6C+ granulocytic myeloid-derived suppressor cells (MDSCs) to the liver of HLA-DR4 transgenic mice. Hepatic MDSCs inhibited SEB-triggered T cell proliferation in a reactive oxygen species–dependent manner, and ex vivo–generated human MDSCs also similarly attenuated the proliferative response of autologous T cells to SEB. We propose a role for MDSCs in mitigating excessive tissue injury during TSS.