Kawasaki syndrome is an acute multisystem vasculitis of infancy and early childhood associated with high fever, mucocutaneous inflammation, and the development of coronary artery abnormalities. Despite the widely held belief that Kawasaki syndrome is an infectious disease, investigations have failed to identify a causal organism. Previous studies have demonstrated that this illness is associated with marked activation of monocyte/macrophages and the selective expansion of Vβ2- and, less so, of Vβ8.1/8.2-expressing T cells in the peripheral blood from Kawasaki syndrome patients during the acute phase of their illness. These immunologic features are characteristic of diseases that are caused by bacterial toxins which act as superantigens. Staphylococcal enterotoxins and streptococcal exotoxins are prototypic superantigens which stimulate large populations of T cells expressing particular T-cell receptorβ-chain variable (Vβ) gene segments. Using the Vβ2⁺ T-cell expansion as an “immunologic footprint” for a superantigen, we have extended these observations to the identification and isolation of a novel clone of toxic shock syndrome toxin-1-producingStaphylococcus aureus in the majority of patients with Kawasaki syndrome and streptococcal pyrogenic exotoxin B/streptococcal pyrogenic exotoxin C-producing streptococci in a minority of Kawasaki syndrome patients. Toxic shock syndrome toxin-1, streptococcal pyrogenic exotoxin B, and streptococcal pyrogenic exotoxin C are known to stimulate Vβ2⁺ T cells. These observations support the hypothesis that the activation of Vβ2⁺ T cells during the acute phase of Kawasaki syndrome is caused by bacterial superantigen(s).