Several studies illustrating idiotype network-directed regulation of the immune response1 have demonstrated that heterologous anti-(anti-idiotype) antibodies (1) share variable (V) region antigenic determinants with idiotype-bearing antibodies2-5, (2) lack antigen-binding activity3-6 and (3) alter the clonal profile of an immune response by stimulating/suppressing regulatory lymphocyte clones of anti-idiotype specificity2-4,6. However, the existence and significance of anti-(anti-idiotype) antibody in natural immunological responses has been questioned because of the artificial immunization procedures used to induce these antibodies. Here we describe a monoclonal mouse anti-(anti-idiotype) antibody generated in physiological conditions by immunizing BALB/c mice with a pneumococcal vaccine that elicits a humoral anti-phosphorylcholine (PC) response dominated by the T15 idiotype7. This antibody recognized an idiotope on a monoclonal anti-T15 antibody, failed to bind PC, did not exhibit detectable idiotypic cross-reactivity with T15 + immunoglobulins, utilized VH and VL genes distinct from the T15 V gene group8, and exerted a suppressive effect on the in vivo response to PC in syngeneic mice. © 1982 Nature Publishing Group.