We report that approximately 1/4 of monoclonal rheumatoid factors produced by hybridomas derived from fusions of spleen cells from MRL/lpr/lpr mice with systemic lupus erythematosus (SLE) and arthritis exhibited multiple reactivities with other autoantigens, including dDNA , histones, and/or cytoskeletal-cytoplasmic elements. The patterns of reactivities of most of these clones differed, indicating that each had a separate B cell ancestor. Studies with eluted antibodies demonstrated that a single species of antibody molecules was responsible for the observed multiple reactivities. Inhibition experiments suggested that an antibody combining site may be large enough to accommodate dissimilar epitopes. These findings may provide further insights into the generation and extent of antibody diversity as well as the etiopathogenesis of systemic autoimmune diseases.