Toxic shock syndrome toxin-1 (TSST-1) isolated from the growth medium of Staphylococcus aureus 1169 and 555 was used to immunize male rabbits before infection with either a TSST-1+ or a TSST-1- strain of S. aureus isolated from cases of TSS. None of the immunized rabbits died as a result of the infections, whereas 50% of the nonimmunized rabbits infected with the TSST-1- strain, D4508, and 75% of those infected with the TSST-1+ strain, 555, died. Western blots of crude extracellular protein preparations probed with sera from immunized rabbits indicated that the TSST-1- strain produces a 30,000-molecular-weight protein that cross-reacts with antiserum to TSST-1. Because both organisms caused similar diseases in rabbits, we propose to designate the cross-reacting protein as TSST-2.