A monoclonal paraprotein in the serum or urine raises the possibility of myeloma. However, in a significant proportion of individuals with serum paraproteins, particularly those with low levels of paraprotein, clinical and routine bone marrow evaluation is not diagnostic of an underlying neoplasm. The purpose of this study was to define the pathologic basis for monoclonal gammopathy in patients whose bone marrow biopsies showed no evidence of myeloma. We used immunofluorescence microscopy and flow cytometry of cell suspensions prepared from aspirated marrow, as well as immunohistochemistry of core biopsies, to perform immunopathologic evaluations of the bone marrow from 26 such patients. Eighteen patients with myeloma and seven without a serum paraprotein or evidence of myeloma were similarly studied. The data indicate that 17 of the 26 patients with monoclonal paraproteins whose routine bone marrow biopsies were normal or nondiagnostic had, in fact, a dispersed monotypic plasma cell population of concordant immunoglobulin heavy and light chain type in the bone marrow demonstrable by at least one of the three analytic methods. Among these, immunofluorescence microscopy of isolated bone marrow mononuclear cells was the most sensitive assay. Immunophenotypic evaluation of the bone marrow is useful for documenting and quantifying a monoclonal plasma cell population in patients with monoclonal gammopathy of undetermined significance.