Two currently used steroids (clobetasone butyrate and betamethasone valerate) reproducibly cause vasoconstriction on topical application to human forearm skin. Progesterone, deoxycorticosterone, testosterone, and estradiol, even at 100- to 200-fold higher concentrations, cause no vasoconstriction when applied alone. Applied with clobestasone butyrate, testosterone and estradiol are without antagonist effect; in contrast, both progesterone and deoxycorticosterone antagonize the vasoconstrictor response in a dose-related fashion, with a half-maximal effect at 20-30 times the concentration of clobetasone. Neither progesterone nor deoxycorticosterone affects the vasoconstriction produced by the intradermal injection of epinephrine. In most glucocorticoid-responsive systems, progesterone and deoxycorticosterone are glucocorticoid antagonists, and estradiol and testosterone are inactive. We interpret these studies as evidence that the vasoconstrictor effects of topical steroids are mediated by occupancy of classical glucocorticoid receptors, rather than by nonspecific pharmacological mechanisms.