In a monoclonal system, F(ab')2 fragments of rabbit anti-mu antibody (anti-mu) were found to inhibit the proliferation and differentiation of highly purified E-rosette-negative largely leukemic B cells from two patients with chronic lymphocytic leukemia (CLL). Leukemic B cells from these two patients, in contrast with the majority of patients with CLL, exhibited high spontaneous proliferation in culture medium alone. This spontaneous proliferation was significantly inhibited by moderate concentrations of anti-mu (10-50 micrograms/ml). In contrast, lower concentrations of anti-mu (0.6-1.2 micrograms/ml) induced proliferation of leukemic B cells. Conditioned media (CM), derived by stimulation of human peripheral blood mononuclear leukocytes with phytohemagglutinin, induced significant proliferation of these leukemic B cells. This induced proliferation at optimal CM concentrations was inhibited by anti-mu. However, at high CM concentrations, which did not cause significant proliferation, synergism between CM and anti-mu in inducing proliferation was observed. Stimulation of spontaneously proliferating leukemic B cells with CM resulted in differentiation into cells synthesizing and secreting immunoglobulin M (IgM) but not IgG. This IgM production was also inhibited by anti-mu.