Summary: Antibodies produced to aggregated human γG-globulin under autologous, isologous and heterologous conditions were compared by contrasting the specificity of antibodies present in rheumatoid arthritic sera, in the serum of a patient with acquired hypogammaglobulinemia and in guinea pig antisera. In each case antibody specific for the aggregated molecule, and exhibiting no affinity for its native form, was produced, and invariably the antigenic determinants eliciting antibody production were located in the Fc region of the aggregated antigen. The antibodies produced under the different conditions were readily distinguishable by their hemagglutination and antigen-binding characteristics. Rheumatoid factor showed species cross reactivity, whereas the anti-isologous and anti-heterologous denatured γG-globulin antibodies were directed entirely against species-specific determinants. Following aggregation of the Fc fragments of HGG, only a portion of the aggregated molecules (about 60%) possessed antigenic determinants capable of reacting with any of the antibodies. Although individual Fc aggregates showing reactivity with one group of antibodies were frequently shown to be antigenic for antibodies of the other groups, a portion of the aggregates reacted exclusively with each of the antibodies. Evidence was presented to suggest that a correlation existed between the antigenic complexity of aggregated Fc fragments and their molecular size. Thus, small Fc aggregates (dimers and trimers) were found to lack antigenic determinants present in larger aggregates (hexamer and greater). It was also shown that many, if not all, of the antigenic determinants revealed by nonspecific denaturation of HGG are also present on the γG-antibody molecule following combination with homologous antigen.