Waldenström macroglobulinemia (WM) is characterized by monoclonal gammopathy, usually IgM, in association with lymphoplasmacytic lymphoma (LPL). Little is known of the expression of nuclear proteins involved in B-cell development in LPL/WM. In this study, the expression patterns of PAX5/BSAP, MUM1/IRF4, and PRDM1/BLIMP1 were analyzed in plasma cells and lymphocytes in 29 cases of newly diagnosed LPL/WM by double immunohistochemical staining with CD138 and CD22. These patterns were compared with the expression profiles seen in normal bone marrow samples, reactive tonsils, and cases of plasma cell myeloma and marginal zone lymphoma. The median percentage of plasma cells coexpressing CD138 and PAX5 was significantly higher in LPL/WM compared with benign tissues (P = .001), marginal zone lymphoma (P = .002), and plasma cell myeloma (P < .0001), whereas the median percentage of plasma cells coexpressing CD138 and MUM1 was lower in LPL/WM than plasma cells in benign tissues (P = .02), marginal zone lymphoma (P = .001), and plasma cell myeloma (P = .0002). These findings show that a subset of plasma cells in LPL/WM demonstrates a nuclear protein expression pattern characteristic of the B-cell developmental program. Thus, the results better define the immunophenotypic profile of the neoplastic cells in LPL/WM.