By using a quantitative immunoblotting technique, we have analyzed the repertoires of antibody reactivities of IgM directed toward self antigens in the serum of patients with Waldenström's macroglobulinemia (WM) and in the serum of healthy adults. Monoclonal IgM of patients with WM expressed various degrees of polyreactivity and a high degree of heterogeneity with regard to the number and the nature of the protein bands that were recognized in homologous tissue extracts. Heterogeneous patterns of reactivity of WM IgM contrasted with the conserved profiles of reactivity of IgM in the serum of healthy blood donors. Protein bands that were recognized by WM IgM belonged to the restricted set of self antigens recognized in homologous tissues by normal polyclonal IgM, indicating the absence of a disease-specific reactivity profile of monoclonal WM IgM. Thus, monoclonal IgM that is present in large amounts in WM distorts the homogeneous pattern of reactivity of natural antibodies with self antigens which characterizes the natural antibody repertoire of healthy individuals.