Superantigens bind class II major histocompatibility proteins and stimulate powerful proliferative responses of T lymphocytes bearing particular V beta sequences as part of their alpha beta antigen receptor. Exogenous bacterial superantigens are responsible for food poisoning and toxic shock syndrome. Murine virus-encoded self-superantigens induce clonal deletion of T lymphocytes. Although superantigen-like properties have been suggested for human immunodeficiency virus-1, no viral superantigen has been identified in humans. Here we report that the nucleocapsid of the rabies virus is an exogenous superantigen specific for V beta 8 human T lymphocytes which binds to HLA class II alpha-chains.