Staphylococcus aureus is one of the most common causes of hospital-acquired infections. At the same time, 25% of healthy persons are symptom-free S. aureus carriers, and they have an increased risk of developing nosocomial S. aureus septicemia. Paradoxically, their prognosis is much better than that of noncarriers. We compared the antibody profiles for carriers and noncarriers toward S. aureus superantigens. In carriers, we found high titers of neutralizing antibodies specific for those superantigens that are expressed by their colonizing strain. The results show that carriage status confers strain-specific humoral immunity, which may contribute to protection during S. aureus septicemia.