We report that sera from healthy controls, patients with ovarian or lung cancer, and patients with rheumatoid arthritis all contain IgM polyclonal rheumatoid factors which recognize antigenic determinants on murine and to a greater extent human immunoglobulin IgG. The major part of this reactivity is directed against conserved, shared antigenic determinants present on both human and murine IgG. Such antigenicity resides in the protein and not the carbohydrate moiety of IgG, since deglycosylation of the target murine monoclonal antibody did not result in any loss of antibody binding. Studies comparing the binding of polyclonal and monoclonal rheumatoid factors (from patients with rheumatoid arthritis and mixed essential cryoglobulinaemia, respectively) to murine and human IgG show that the antigenic determinants recognized by polyclonal rheumatoid factors are present on both whereas the antigenic determinant recognized by the monoclonal rheumatoid factors is present only on human IgG. Furthermore, patients with rheumatoid arthritis display an elevated human IgM anti-murine immunoglobulin response similar to that seen in cancer patients who have received murine monoclonal antibody therapy. We therefore conclude that, where possible, F(ab')2 fragments of murine monoclonal antibodies should be used for in vivo tumor localization studies to avoid possible immune complex formation, and that patients with rheumatoid arthritis should be considered to be possibly at higher risk of developing immune complex disease, were these rheumatoid factors to bind to the administered murine antibodies in vivo.