Recent evidence suggests that certain periodontal pathogens preferentially stimulate T cells expressing specific variable regions on the  chain (V) of the T-cell receptor, which may indicate the presence of a superantigen. Superantigens are microbial proteins that activate large numbers of CD4⁺ T cells in a V-specific manner. The purpose of this study was to determine whether Prevotella intermedia, a putative periodontal pathogen, activates populations of specific V on CD4⁺ T cells. Among the bacterial strains tested, P. intermedia strain 17, a clinical isolate, induced the strongest proliferative response in peripheral blood mononuclear cells. Antibodies raised against whole cells of this organism blocked the proliferative activity. P. intermedia-induced proliferation was T-cell specific and required the presence of antigen-presenting cells. Flow cytometric analysis showed that CD4⁺ T-cell subsets expressing V8, V12, and V17 expanded in response to P. intermedia strain 17. The ability of P. intermedia to stimulate CD4⁺-T-cell proliferation was further supported by the production profiles of key T-cell cytokines, gamma interferon and interleukin-2. The data collectively suggest that certain strains of P. intermedia can activate V-specific T cells in a manner similar to that of other known microbial superantigens.