The maturation of malignant cells in response to differentiating agents is interesting as a model of normal differentiation. The response of a freshly explanted neoplastic population of phenotypically well- characterized lymphosarcoma cell leukemia blasts was studied after incubation with the differentiating agent TPA (12–0-tetradecanoyl- phorbol-13-acetate). Terminal differentiation was assessed by measuring the immunoglobulin secreted in culture supernatants and the production of intracytoplasmic immunoglobulins. Activation of the cells was studied using fluorescein-labeled monoclonal antibodies to various antigens in a flow cytometer (fluorescence-activated cell sorter) and 3H-thymidine (3H-Tdr) incorporation was evaluated to measure DNA synthesis in cells grown in complete medium and TPA-supplemented medium. The events induced by TPA were characteristic of B cell maturation and included morphological changes to plasmacytoid cells, reduction in surface immunoglobulins (sIgM, sIgD, and K), enhancement of cytoplasmic immunoglobulin, and amplification of immunoglobulin secretion. Surface antigen changes were accompanied by increased 3H-Tdr incorporation. Cell proliferation and differentiation appeared to be coupled and both were amplified by TPA treatment. These observations indicate that TPA can promote maturation of malignant secretory B cells to a terminal differentiation stage. The significance of these findings to normal B cell differentiation and their potential clinical utility is discussed.