To test the clinical relevance of monoclonal anti-I-A antibody in autoimmune disease, we investigated the effects of such a therapy in acute and chronic relapsing experimental allergic encephalomyelitis (EAE) by instituting treatment after the onset of paralytic signs and following the clinical course. In chronic relapsing EAE, animals treated with anti-I-As antibody had no mortality and fewer relapses when compared with control animals. Antibody levels to myelin basic protein were lower and histopathology showed milder lesions in the treated group. Similarly, in the acute EAE model, animals treated with anti-I-As antibody showed a dramatic reversal of paralytic signs and a rapid recovery. The mechanisms of action of antibody to IR gene products in autoimmune disease are discussed.