H erpesvirus entry mediator (HVEM), a TNF receptor superfamily member, has been previously described as a T cell costimulatory receptor. Surprisingly, HVEM–/– T cells showed enhanced responses to in vitro concanavalin A (ConA) stimulation when compared with WT T cells. Consistent with these findings, HVEM–/– mice exhibited increased morbidity and mortality as compared with WT mice in a model of ConA-mediated T cell–dependent autoimmune hepatitis. HVEM–/– mice produced higher levels of multiple cytokines, which were dependent on the presence of CD4⁺ T cells. Furthermore, HVEM–/– mice were more susceptible to MOG peptide–induced experimental autoimmune encephalopathy, and they showed increased T cell proliferation and cytokine production in response to antigen-specific challenge. Taken together, our data revealed an unexpected regulatory role of HVEM in T cell–mediated immune responses and autoimmune diseases.