Herpesvirus 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.