The structural basis of the double reactivity of a human monoclonal rheumatoid factor (RF) with both human IgG and histones H1 and H3 was investigated by means of competitive inhibition experiments. The monoclonal RF binding to solid-phase histones was inhibited by increasing concentrations of heat-aggregated IgG. However, increasing concentrations of purified histones were almost unable to reduce the RF binding to solid-phase IgG. Inhibition of antigen binding with two murine monoclonal anti-idiotopes reacting with distinct idiotopes on the monoclonal RF indicated that the fixation to the different antigens was mediated by distinct binding sites. This result was confirmed by showing the selective sensitivity to mild acid treatment of the histone binding site but not of the IgG binding site. This report provides a structural basis for the existence of polyfunctional combining regions on a human autoantibody.