We have previously reported that a complementary peptide (denoted RhCA 67- 16), encoded by RNA complementary to that of the Torpedo acetylcholine receptor (AChR) main immunogenic region (MIR), AChR residues α61-76, induces polyclonal and monoclonal Ab reactive with Ig against the AChR MIR. RhCA 67- 16 vaccination also protected against the development of experimental autoimmune myasthenia gravis (EAMG) in Lewis rats. In the present report, we found that a mAb (denoted TCM 240, IgG1κ) against RhCA 67-16 recognized three different idiotypic Ab (mAb 6, mAb 35, and mAb 198), which were previously reported by others to recognize the AChR MIR and to cause EAMG. Based on these results, TCM 240 was tested for prophylactic effects in EAMG. EAMG induced passively by mAb 35 was inhibited by simultaneous injection with TCM 240. The disease severity was inversely paralleled by the ratio of mAb 35 to TCM 240. EAMG induced by immunization with purified native Torpedo AChR was also inhibited by TCM 240, but not a control mAb. The inhibitory effect of TCM 240 on actively induced EAMG occurred without significantly lowering the overall AChR Ab levels, which indicates a limited repertoire of disease- causing Ab in EAMG and perhaps MG. Such findings suggest the existence of an EAMG-associated Id and also support the concept of an MIR. In a more general sense, these results demonstrate that prophylactic and perhaps diagnostic mAb for autoimmune diseases can be produced by immunization with complementary peptides for disease-associated epitopes.