Anti-idiotypic antibodies may regulate the immune system and influence pathogenic autoimmunity. We investigated idiotype–anti-idiotype interactions in sera of patients with primary biliary cirrhosis (PBC), normal subjects and animals immunized with pyruvate dehydrogenase complex (PDC) or its derivatives. IgG autoantibody to the E2 subunit of PDC (PDC-E2) was derived by affinity-purification from sera of 12 patients with PBC, and F(ab)2 was prepared (anti–PDC-E2-F[ab]2). This was used as a reactant by enzyme-linked immunosorbent assay (ELISA) with sera from patients with PBC, normal subjects, or immunized animals. Results were that IgG antibody to anti–PDC-E2-F(ab)2 was detectable at low concentration in 12 PBC sera (mean optical density [OD] ± SD: 1.02 ± 0.26), and also in 19 normal sera (mean OD ± SD: 0.97 ± 0.35) using a serum dilution of 1:20; background OD was 0.09 to 0.10, whereas antisera from animals immunized with PDC or PDC-E2 were nonreactive. There was a significant inverse correlation (r = −.59, P = .04) between the levels of anti–PDC-E2 in PBC sera (but not normal sera), and anti-idiotypic antibody reactive with anti–PDC-E2-F(ab)2. Anti-idiotypic antibody existed as a complex with anti–PDC-E2, because the removal of anti–PDC-E2 from serum resulted in decreased reactivity to anti–PDC-E2-F(ab)2. Reactivity between PDC-E2 and anti–PDC-E2 from PBC serum was not inhibited by normal sera, indicating that anti-idiotypic antibody from normal sera with anti–PDC-E2 reacts with the framework of F(ab) rather than the paratope. The conclusions are that PBC and normal sera contain IgG class anti-idiotypic antibodies to anti–PDC-E2, the characteristic autoantibody in PBC. Anti–PDC-E2 in immunized animals does not contain an idiotype cross-reactive with human anti–PDC-E2. Anti-idiotypic antibody in PBC is complexed with anti–PDC-E2 and in part accounts for immune complexes demonstrable in PBC. Anti-idiotypic antibody in PBC may regulate levels of anti–PDC-E2.