Toxic shock syndrome (TSS) is an acute toxin-mediated illness resulting in multiorgan failure and shock. It is caused by toxin-producing strains of S aureus and Streptococcus pyogenes (group A Streptococcus). Although menstrual staphylococcal TSS appears to be more commonly known because of its association with tampon use, as discovered in the 1980s, nonmenstrual staphylococcal TSS is more prevalent and associated with a higher mortality than menstrual TSS. Nonmenstrual staphylococcal TSS is caused by any primary infection or even colonization with a toxin-producing strain of S aureus, which can be seen with any skin disruption or abscess. The mechanism of this syndrome is related to the excessive proliferation and activation of T cells, leading to a surge in cytokine and chemokine release that causes widespread inflammation. The major toxins produced by S aureus are toxic shock syndrome toxin-1 (TSST-1) and staphylococcal enterotoxin B (SEB). TSST-1 is responsible for 50% of nonmenstrual staphylococcal TSS. These toxins act as superantigens and bypass conventional antigen processing, thereby activating nearly 30% of host T cells, whereas, normally, only 0.01% of T cells are activated after conventional antigen processing. The activation of T-helper 1 cells leads to release of IL-1, IL-8, and tumor necrosis factor, which act synergistically to produce the clinical manifestations of toxic shock. In addition, TSST-1 has been shown to suppress specific antitoxin immunoglobulin production by inducing apoptosis of T-cell-dependent B cells.