A/J mice were found to produce autoreactive IgM anti-IgG1 in response to secondary immunization with a number of protein antigens. No anti-IgG1 was produced after a single such immunization, indicating that antigen: IgG1 antibody complexes were responsible for inducing the autoreactive response. The size of the anti-IgG1 response was in some cases massive and of the same order of magnitude as the response to the foreign immunizing material. No significant anti-IgG2a, anti-IgG2b, or anti-IgG3 response was found in mice producing anti-IgG1. Virtually all of the anti-IgG1 material produced was of the IgM class and bound to the Fc region of autologous IgG1. A component of the anti-IgG1 was shown to be able to distinguish between the two mouse IgG1 allotypes. These results suggest that self-reactive anti-IgG is a common component of the secondary immune response of mice that may have powerful physiological and immunoregulatory effects.