Antibodies to the F (ab') 2 portion of IgG were detected in the sera of patients and normals using a heat-aggregated F (ab') 2 fragment in a liquid-phase radioimmunoassay. The antibodies were found in 72% of 82 rheumatoid arthritis patients, in less than 20% of patients with other diseases and in a few normal subjects. Anti-F (ab') 2 antibodies were distinct from previously described anti-Fc antibodies and'serum agglutinators'. They reacted with intact IgG, F (ab') 2 and IgM in binding and inhibition assays and they appeared to have specificity for the Fd portion of IgG molecules, possibly to the VH region. The anti-F (ab') 2 antibodies were of both 7S IgG and 19S IgM classes and were found in sera as components of intermediate size (between 7S and 19S) and large size (greater than 19S) immune complexes. The possible contribution of autologous anti-F (ab') 2 to abnormal immunoregulation is discussed.