The occurrence of multiple myeloma (MM) and a second B-cell neoplasm in the same patient is a rare event. We present 2 such patients, and provide evidence to support the presence of separate clones in these coexisting neoplasms. In the first case, MM became evident 14 months after the diagnosis of chronic lymphocytic leukemia (CLL). In past reports, most occurrences of this association, when investigated, have been regarded to be biclonal disease processes; however, with few exceptions, most were documented by immunologic studies alone. To establish the clonality in our case of CLL with MM, we examined both immunophenotypic data obtained by standard two-color flow cytometric analysis, and patterns of immunoglobulin gene rearrangement, using standard Southern analysis and hybridization with 32P-labelled JH and JK probes. This provided evidence for the presence in this patient of two separate monoclonal populations of B cells, manifested as light chain restrictions and gene rearrangements which differed in blood (CLL) and bone marrow (MM) samples. In the second case, MM presented simultaneously with bone marrow lymphocytosis and abnormal peripheral lymphocytes. Clonality studies on blood were not done. Bone marrow B-cell gene rearrangement studies, however, revealed the presence of three bands in the JK blot of significantly different intensities, suggestive of two monoclonal populations. A monoclonal population of small cells with surface B markers and surface IgM was demonstrated by flow cytometry, while a second population of larger cells with intracytoplasmic IgG matching the patient's serum monoclonal protein was detected by immunofluorescence microscopy. The results in these 2 cases expand previous findings of the rare association of MM with a second B-cell neoplasm, and demonstrate the usefulness of molecular diagnostic investigation.