Mycoplasma arthritidis induces a chronic arthritis in rodents. The role of M. arthritidis-derived superantigen (MAS) in the arthritis is still a subject of controversy. MAS stimulates mouse and human T cells in a V beta-restricted manner with the subsequent liberation of cytokines. The presence of the major histocompatibility complex class II molecule is required for such a stimulation. In this study we assessed MAS-induced cytokine production in peripheral blood from patients with different rheumatic diseases and controls using an enzyme-linked immunosorbent assay. Statistically significant differences in cytokine production in response to MAS stimulation allowed the distinction of high responders and low responders within groups of patients and controls. Higher cytokine induction was statistically correlated with the HLA-DR specificities DR4, DR7 and DR12. To confirm these results, murine V beta 8.1 cytotoxic T lymphocytes (CTL) were stimulated with MAS in the presence of different HLA-DR lymphoblastoid B cells. CTL proliferation was only observed in presence of DR4 and DR7. In conclusion, MAS T cell stimulation and its subsequently cytokine production depends on the presence of certain HLA-DR specificities.