Tumor necrosis factor receptor-1 (TNFR1, CD120a) has been implicated in the pathogenesis of several experimental models of T cell-mediated autoimmune disorders, but its role in antibody-mediated autoimmune diseases has not been addressed. Experimental autoimmune myasthenia gravis (EAMG), an autoantibody-mediated T cell-dependent neuromuscular disorder, represents an animal model for myasthenia gravis in human. To investigate the role of TNFR1 in the pathogenesis of EAMG, TNFR1^–/– and wild-type mice were immunized with Torpedo acetylcholine receptor (AChR) in complete Freund's adjuvant. TNFR1^–/– mice failed to develop EAMG. Lymphoid cells from TNFR1^–/– mice produced low amounts of T_h1 (IFN-γ, IL-2 and IL-12)-type cytokines, but elevated levels of T_h2 (IL-4 and IL-10)-type cytokines compared with lymphoid cells of wild-type mice. Accordingly, the levels of anti-AChR IgG2 antibodies were severely reduced and the level of anti-AChR IgG1 antibodies were moderately reduced. Co-injection of recombinant mouse IL-12 with AChR in adjuvant restored T cell responses to AChR and promoted development of EAMG in TNFR1^–/– mice. These results demonstrate that the TNF/TNFR1 system is required for the development of EAMG. The lack of a functional TNF/TNFR1 system can, at least in part, be substituted by IL-12 at the stage of initial priming with AChR and adjuvant.