Although IL-12 is known to enhance IFN-gamma synthesis in unprimed CD4+ T cells, the effect of IL-12 on IL-4 synthesis in primed CD4+ T cells, which are thought to have relatively fixed cytokine profiles, has not been clearly examined. We examined the effects of IL-12 on cytokine production by CD4+ keyhole limpet hemocyanin (KLH)-primed memory lymph node T cells and by already established KLH-specific CD4+ T cell clones. First, we found that the presence of IL-12 greatly reduced the development of IL-4 synthesis in resting but not activated memory CD4+ T cells. Although IL-12 did not inhibit the production of IL-4 in cloned Th2 effector cells, it greatly inhibited the development of IL-4 synthesis in primed CD4+ T cells taken from the lymph nodes of mice previously immunized with KLH. Secondly, we found that IL-12 inhibited IL-4 synthesis either when directly added to cultures of T cells or when APC were preincubated in IL-12. Inasmuch as the enhancing effect of IL-12 on IFN-gamma synthesis occurred optimally only when the T cells were cultured directly in IL-12, these studies indicate that IL-12 affects IL-4 synthesis via a mechanism that involves APC, a process that differs from that by which it affects IFN-gamma synthesis. These studies also indicate that the administration of IL-12 would be clinically useful in treating patients, for example those with allergic disease or lepromatous leprosy, in whom memory T cells inappropriately overproduce IL-4.