In order to compare the actions of interferons on the various pathways leading to human B-cell activation, we examined the effects of alpha-interferon (INF-alpha), beta-interferon (INF-beta), and gamma-interferon (INF-gamma) on B-cell responses to mitogenic stimuli which differ in their mode of B-cell stimulation. Utilizing highly purified small, dense peripheral blood B-cells or splenic lymphocytes, we demonstrate that (i) INF-alpha, -beta, and -gamma enhance human B-cell proliferation induced by cross-linking of surface Ig with either SAC or anti-mu in a dose-dependent fashion, analogous to and with a magnitude equal to or greater than that seen with human B-cell growth factor; (ii) INF-alpha and -beta but not IFN-gamma inhibit phorbol myristate acetate-mediated B-cell mitogenesis, again in a dose-dependent manner; and (iii) IFN-gamma does not effect B-cell cytoplasmic calcium ([Ca2+]i) influx, either in the resting state or following stimulation with anti-mu, making it unlikely that IFN-gamma exerts its stimulatory effects on B-cell function through changes in [Ca2+]i. Taken together, these findings suggest that all three types of interferons may have important immunoregulatory roles in B-cell activity, and that their ability to enhance or suppress B-cell activation depends on the nature of the mitogenic stimulus.