Superantigens exert their pathologic effects by direct binding to major histocompatibility complex (MHC) class II molecules and T cell antigen receptors (TCR), thus circumventing the normal, antigen-specific immune response. A direct link between disease and toxin suggests an excellent opportunity for vaccine intervention. Site-directed mutants of staphylococcal enterotoxin A (SEA) that have attenuated binding to either the TCR or the MHC class II molecule were developed. Both kinds of SEA mutants induced high levels of antibody against SEA when used as vaccines, and the immunized animals were fully protected when challenged with wild type toxin. However, a residual lethality was associated with the attenuated TCR-binding mutant. These results, combined with an understanding of the molecular nature of superantigen and receptor interactions, indicate that targeting MHC class II binding by site-directed mutagenesis will produce the most effective vaccine.