Staphylococcal exotoxins are virulence determinants in Staphylococcus aureus arthritis and septicemia. To assess the utility of enterotoxins as vaccine candidates for these diseases, a genetically modified staphylococcal enterotoxin A (SEA) that lacks superantigenic properties was used. Mice immunized with recombinant (r) SEA had significantly longer survival than control immunized mice and lost significantly less weight than the controls. Transfer of SEA-specific antibodies to naive mice resulted in good protection against death in staphylococcal sepsis. In vitro proliferative responses to SEA by naive lymphocytes were almost totally abolished on incubation with serum from rSEA but not with control antigen-immunized mice. These results suggest that immunization with rSEA devoid of superantigenic properties provides good protection against S. aureus sepsis. In addition, the data indicate that the protection is at least in part mediated by SEA neutralizing antibodies.