Specific immunosuppression of experimental autoimmune myasthenia gravis (EAMG) was achieved by the use of a denatured preparation of the acetylcholine receptor (AcChoR) that did not in itself induce the disease. Torpedo californica AcChoR was irreversibly denatured by complete reduction and carboxymethylation in 6 M guanidine hydrochloride. Rabbits immunized with reduced carboxymethylated receptor (RCM-AcChoR) produced antibodies that reacted with both RCM-AcChoR and intact AcChoR. The specificity of anti-RCM-AcChoR antibodies is different from that of anti-AcChoR antibodies because the former are directed to only part of the antigenic determinants present in the intact receptor. RCM-AcChoR, which by itself is completely nonmyasthenic, was shown to be capable of both preventing the onset of EAMG and of reversing the clinical symptoms in myasthenic rabbits. In all cases the therapeutic effect of RCM-AcChoR administration on EAMG was accompanied by a change in the immunological specificity of the antibodies. The crossreactivity between AcChoR and RCM-AcChoR and the nonpathogenicity of RCM-AcChoR appear to be crucial in governing the specific immunosuppressive effects of RCM-AcChoR on EAMG.