This study was undertaken to determine whether the commonly used treatment of psoriasis with potent topical glucocorticoids results in hypercortisolism and whether metabolic changes might provide a means for monitoring pharmacologic effects of excessive systemic absorption of glucocorticoids. Plasma cortisol, glucose, and insulin and circulating polymorphonuclear leukocytes were assessed under controlled conditions in five otherwise healthy patients with psoriasis (40% to 85% involvement) treated with topical desoximetasone, without occlusion. In all patients, there were rapid and sustained suppression of endogenous cortisol production, twofold to threefold increases in fasting insulin levels indicating insulin resistance, and elevated levels of polymorphonuclear leukocytes. Two patients also experienced reduced glucose tolerance. These findings suggest that application of potent corticosteroids to large areas of diseased skin results in sufficient systemic absorption to cause not only adrenal suppression but some degree of hypercortisolism with greater frequency and rapidity than has been suggested. Prospective monitoring of insulin-glucose relationships as a sensitive index of the metabolic effects of glucocorticoids may provide a means of assessing excess systemic absorption that is not predictable on the basis of adrenal suppression or circulating levels of the drug. Such prediction could have particular relevance in anticipating adverse clinical effects in the treatment of chronic skin disorders with potent topical glucocorticoids.