The exact mechanism of the beneficial therapeutic action of interferon-a (IFN-alpha) in B-cell-lineage malignancies has not been adequately explained. Here we report on the differential effect of IFN-alpha2b on non-malignant B cells of umbilical cord blood and leukemic B-cell lines JY, BL-41 and BCBL-1. Leukemic cell proliferation was characterized by colony assay, whereas apoptosis was investigated by flow cytometry of propidium iodide-stained cells. The degree of differentiation was evaluated by measuring the expression level of Fcgamma receptor-II (FcgammaRII) labeled with anti-CD32-FITC monoclonal antibody using flow cytometry. IFN-alpha protected umbilical cord blood CD19-positive B lymphocytes from apoptotic cell death in vitro. IFN-alpha significantly decreased colony formation of all three cell lines, and in contrast to normal cells, induced apoptosis in JY and BL-41 and excessive necrosis in HHV-8 infected BCBL-1 cells. FcgammaRII was upregulated both in normal and in leukemic B cells as indicated by an increase both in the proportion of CD32-positive cells and the mean fluorescence intensity. From our results it seems that antiproliferative, apoptotic and differentiative effects of IFN-alpha are interrelated but distinct cellular events, which are differentially regulated in normal, leukemic and virus-infected cells of the B-cell lineage.