Anti-red blood cell (RBC) immunoglobulin G (IgG) autoantibodies are present in patients with warm autoimmune haemolytic anaemia (WAIHA), and, as natural autoantibodies, in healthy individuals. This study investigated whether the feature of polyreactivity discriminates disease-associated from natural anti-RBC IgG autoantibodies. The patterns of reactivity of puri®ed anti-RBC IgG eluted from the RBC of WAIHA patients and from the RBC of healthy individuals were analysed using quantitative immunoblotting on a panel of whole human tissue or bacterial cell extracts as antigen sources. In parallel, the reactivity patterns of IgG puri®ed from plasma were analysed. Anti-RBC IgG of WAIHA patients and of healthy individuals recognized a wide range of self-and nonself-antigens. The reactivity patterns of anti-RBC IgG were homogeneous among patients and controls, did not differ between patients and controls, and were similar to those of IgG puri®ed from plasma in the case of both patients and healthy individuals. The data demonstrate that the anti-RBC IgG autoantibodies of WAIHA patients share extensive similarity with those of healthy individuals. Polyreactivity is a common feature of both disease-associated and natural anti-RBC IgG autoantibodies.