Waldenström's macroglobulinemia (WM) is a malignant lymphoplasmo-proliferative disorder with monoclonal pentameric immunoglobulin (Ig)M production. The most consistent feature of clonal B cells in the bone marrow (BM) and/or lymph nodes of patients with WM is the presence of pleomorphic B-lineage cells at different stages of maturation, such as small lymphocytes, lymphoplasmacytoid cells, and plasma cells. Monoclonal lymphocytes express mu chains with or without delta chains. A recent DNA analysis of WM tumor clones showed WM to be derived from B cells that have been selected by antigen at a relatively late stage of differentiation. To further clarify the origin of WM tumor cells, we analyzed the variable (V) domain sequences of tumor derived mu and delta transcripts. The expression of delta transcripts was also examined in peripheral blood (PB) and BM using the reverse transcriptase polymerase chain reaction (RT-PCR) combined with a single-strand conformation polymorphism (SSCP) analysis. The sequences were identical among the mu and delta transcripts in each patient and the level of somatic mutation in the VH regions expressed by tumor cells was in the same range as that of IgM-only B cells and IgM(+)IgD(+) memory B cells. In our previous RT-PCR-SSCP analysis, a single dominant band of the mu isotype was observed in BM and PB in all patients. However, common dominant bands in BM and PB were detected in only one patient in a delta transcript analysis. In the rest of the patients, monoclonal delta transcripts were only detected in BM. Our results suggest that a normal counterpart of WM cells is somatically mutated IgM(+)IgD(+) and/or IgM-only B cells and the expression patterns of monoclonal mu and delta transcripts differ between BM and PB in some cases of WM.