We investigated the effects of corticosteroids on IL-12 production by mouse splenic adherent cells and the subsequent capacity of these cells to induce cytokine production by CD4+ T cells. To distinguish the effects of corticosteroids on APCs from those on T cells, only the APCs and not the T cells were exposed to corticosteroids. Treatment of splenic adherent cells with dexamethasone greatly inhibited production of IL-12, a cytokine known to enhance IFN-γ synthesis and decrease IL-4 synthesis by CD4+ T cells. The reduction in IL-12 production by corticosteroid-treated macrophages decreased their ability to induce IFN-γ and increased their ability to induce IL-4 synthesis in Ag-primed CD4+ T cells. Splenic adherent cells from mice treated in vivo with dexamethasone also displayed a reduced capacity to produce IL-12. These results help to resolve previous conflicting observations regarding the effects of corticosteroids on cytokine production by T cells, and indicate that while corticosteroids may directly inhibit Th1 and Th2 cytokine production in T cells, corticosteroids, by reducing IL-12 production in APCs, have the potential to indirectly enhance Th2 cytokine synthesis. Therefore, treatment of diseases such as allergy with chronic corticosteroids may indirectly exacerbate the course of the disease, which is caused primarily by the overproduction of Th2 cytokines in allergen-specific CD4+ T cells.