Kawasaki disease (KD) is a multisystem vasculitis and the leading cause of acquired heart disease in children of the developed world. Lactobacillus casei cell wall extract-induced coronary arteritis in mice mirrors KD in children. Here, we report that responses to L. casei cell wall extract possess all the hallmarks of a superantigen-mediated response: marked proliferation of naive T cells, non-classical major histocompatibility restriction with a hierarchy in the efficiency of different class II molecules to present this superantigen, a requirement for antigen presentation, but not processing, and stimulation of T cells in a non-clonal, TCR V(beta) chain-dependent fashion. This superantigenic activity directly correlates with the ability to induce coronary arteritis in mice. Taken together, our findings demonstrate that superantigenic activity in L. casei cell wall extract is responsible for induction of coronary artery disease.