Staphylococcus aureus can produce a wide variety of exotoxins, including toxic shock syndrome toxin 1 (TSST-1), staphylococcal enterotoxins, and staphylococcal enterotoxin-like toxins. These toxins share superantigenic activity. To investigate the beta chain (Vbeta) specificities of each of these toxins, TSST-1 and all known S. aureus enterotoxins and enterotoxin-like toxins were produced as recombinant proteins and tested for their ability to induce the selective in vitro expansion of human T cells bearing particular Vbeta T-cell receptors (TCR). Although redundancies were observed between the toxins and the Vbeta populations, each toxin induced the expansion of distinct Vbeta subsets, including enterotoxin H and enterotoxin-like toxin J. Surprisingly, the Vbeta signatures were not associated with a specific phylogenic group of toxins. Interestingly, each human Vbeta analyzed in this study was stimulated by at least one staphylococcal superantigen, suggesting that the bacterium derives a selective advantage from targeting the entire human TCR Vbeta panel.