A network of idiotypes and anti-idiotypes has been hypothesized to modulate antibody production against exogenous antigens. Idiotypic antigens on autoantibodies have been studied because of their potential use for specific immunomodulation. The present studies describe the preparation and characterization of rabbit anti-idiotypic antibody against human IgM anti-IgG autoantibodies (rheumatoid factors, RF) that bear the "internal image" of the human IgG-Fc fragment, and hence react specifically with the majority of RF from patients with rheumatoid arthritis. The anti-idiotype was isolated from rabbit anti-RF antisera by either immunodepletion of anti-immunoglobulin antibodies, or more simply by a single affinity purification step on a rabbit anti-human IgG Fc column. As measured by an enzyme-linked immunoassay, the anti-idiotype prepared by both methods bound to plates coated with purified IgM RF, but not to plates coated with non-RF IgM proteins. The anti-idiotype dose dependently blocked the binding to IgG of IgM-RF in 83% of sera from multiple patients with rheumatoid arthritis, Sjogren's syndrome, and macroglobulinemia. The anti-idiotype did not inhibit the activity of human IgM antibodies against DNP, tetanus toxoid, or thyroglobulin. The antigen recognized by the cross-reactive anti-idiotype was not apparently associated with a particular light or heavy chain amino acid sequence, but rather was intrinsic to most immunoglobulins with RF activity. Broadly cross-reactive anti-idiotypes with the "internal image" of IgG are simple to generate, and react with most RF. They may facilitate studies on the specific regulation of the human anti-IgG autoantibody response.