Few risk factors for nonmenstrual toxic shock syndrome (TSS) have been identified. This study sought to determine at what rate and under what circumstances nongenital toxigenic Staphylococcus aureus infections led to TSS. Clinical isolates of S. aureus were examined for the production of TSS toxin 1 (TSST-1), and available sera from infected patients were tested for antibody to this toxin. Twenty-six percent of 810 isolates produced TSST-1. Isolates from children were more likely to be positive for TSST-1 than were those from adults. None of 57 patients with TSST-1-positive staphylococcal infection and a TSST-1 antibody titer of greater than or equal to 1:100 developed TSS. Eight of 65 tested patients with TSST-1-positive isolates had antibody below the presumably protective level of 1:100. Two of these patients had definite TSS, three had probable or possible TSS, and three probably did not have TSS. In patients lacking protective antibody to TSST-1, the interval between acquisition and infection with staphylococci, the type and amount of toxins produced, the site of infection, and still-unclarified aspects of host susceptibility may all affect the rate and severity of TSS.