Antibody directed against HBsAg carries idiotypic determinants that may induce an autoantiidiotype antibody response. We describe a solid-phase radioimmunoassay which allows specific detection of either IgG or IgM antibody to antibody directed against HBsAg. Among 138 chronic hepatitis B virus carriers, IgG autoantiidiotype was detected in 98 (71%) and IgM autoantiidiotype in 110 (80%). The autoantiidiotype reaction was blocked with antibody directed against HBsAg after removal of immune complexes by polyethylene glycol precipitation. The prevalence and levels of both classes of autoantiidiotype antibodies were highest in patients with hepatitis B virus DNA or HBeAg in serum. During follow-up, patients who lost hepatitis B virus DNA and HBeAg from serum had lower titers of autoantiidiotype and were less likely to have autoantiidiotype than patients who persisted in having hepatitis B virus DNA and HBeAg in serum. Thus, the presence and titer of autoantiidiotype correlated with serologic evidence of active viral replication in chronic hepatitis B. These findings suggest that the antibody directed against HBsAg response may play a role in modulating viral replication in chronic hepatitis B.