To provide direct genetic evidence for a role of IL-6 in experimental autoimmune myasthenia gravis (EAMG), IL-6 gene KO (IL-6−/−) mice in the C57BL/6 background were immunized with Torpedo californica acetylcholine receptor (AChR) and evaluated for EAMG. Only 25% of AChR-immunized IL-6−/− mice developed clinical EAMG compared to 83% of C57BL/6 (wild-type) mice. A significant reduction in the secondary anti-AChR Ab of IgG, IgG 2b, and IgG 2c, but not the primary or secondary IgM response was observed in AChR-immunized IL-6−/− mice, suggesting a possible defect in T cell help and class switching to anti-AChR IgG 2 isotype. The AChR-specific lymphocyte proliferative response, IFN-γ, and IL-10 production were suppressed in AChR-immunized IL-6−/− mice. EAMG resistance in IL-6−/− mice was associated with a significant reduction in germinal center formation and decreased serum complement C3 levels. The data provide the first direct genetic evidence for a key role of IL-6 in the autoimmune response to AChR and in EAMG pathogenesis.