It is being increasingly recognized that interleukin (1L)-12 has profound influences in regulating not only cellular immunity, but humoral immunity as well. The precise effects of IL-12 on B-cell activity and the mechanism (s) responsible for them, however, remain unclear. Some groups have previously reported that the primary effect of IL-12 on B cells is suppression of Ig production,'^'particularly of Th2-associated isotypes (IgG1 and IgE in the mouse). Conversely, we and others have found that IL-12 administration enhances production of nearly all Ig i~ otypes.~.~ Furthermore, the role of interferon (1FN)-y in mediating these effects is uncertain, since in many cases, the ability of 1L-12 to influence humoral immunity is either not affected'.'or incompletely inhibited'by anti-IFN-y antibodies. In this paper, we describe our studies, which deal with the ability of IL-12 to modify in uiuo and in uitro activities of B-cell subsets. The results of these experiments have led to us to formulate a hypothesis that explains the apparent paradoxical findings regarding the action of IL-12 on B cells.