Glucocorticoids are widely used in the therapeutic intervention of allergic diseases, affecting the function of a variety of proinflammatory cell types that participate in these disorders. These drugs have been shown to inhibit the release of histamine by human basophils, but not by mast cells, in a reaction requiring 8 to 24 h. To address whether the generation of IL-4 by basophils is similarly affected, we investigated the actions of glucocorticoids on the in vitro release of this cytokine induced by anti-IgE Ab or by the human recombinant histamine-releasing factor. The ability of basophils to generate IL-4 was immediately affected, with secretion of this protein being inhibited >50% with <1-h preexposure to steroid. However, the release of histamine in these cultures was inhibited only after 24-h preincubation, suggesting that the mechanisms controlling the release of this mediator differ significantly from those regulating cytokine secretion. A rank order of potency of the steroids tested for inhibition of IL-4 protein was as follows: triamcinolone > dexamethasone > betamethasone > hydrocortisone. The sex steroids, testosterone and estrogen, showed no effect on basophil secretion. Experiments using reverse transcription-PCR indicate that glucocorticoids inhibit IL-4 generation in basophils on the level of transcription. These studies suggest that the success of glucocorticoids in the treatment of allergic conditions is due in part to their ability to inhibit both mediator release and cytokine secretion by basophils.