In vitro hydrocortisone, in pharmacologically attainable concentrations, binds nonspecifically to rat peritoneal mast cells and amplifies the stimulating effects of PGE1 on membrane-bound adenylate cyclase. As a consequence, the intracellular concentration of cyclic AMP in the target cells increases and histamine release is markedly reduced. Deoxycorticosterone, at the same concentrations, has no effect. These findings may in part explain the mechanism of action of anti-inflammatory steroids, possibly related to the modulating effects of E-type prostaglandins.