We studied the effects of administration of dexamethasone, 2 mg orally every 6 hr for 4 doses, on circulating thyroid hormone levels in hyperthyroid Graves' disease patients and in normal subjects. Serum triiodothyronine (T3), thyroxine (T4) and thyroglobulin (Tg) fell significantly below baseline values within 24 to 48 h after the first dose of dexamethasone in hyperthyroid patients; the values returned to or toward baseline levels in the subsequent 5 to 6 days. Serum T3 fell transiently in normals but to a much smaller degree than in hyperthyroid patients; T4 and Tg showed no significant change. Dexamethasone had ni inhibitory effect on the thyroid response to exogenous TSH in the hyperthyroid patients. Studies in vitro demonstrated lack of any appreciable effect by dexamethasone or hydrocortisone on stimulation of human thyroid adenyl cyclase by TSH or immunoglobulin G(IgG) from patient with Graves' disease. The fall in serum T3 without a change in serum T4 in normals suggested an effect of dexamethasone on peripheral conversion of T4 to T3. However, the markedly greater, more persistent drop in T3 in the hyperthyroid patients, as well as the associated drop in T4 and Tg, suggested an additional effect of dexamethasone administration on thyroid secretion in these patients. Preservation of thyroidal response to TSH during dexamethasone administration both in vivo and in vitro indicated that dexamethasone had not impaired thyroidal cellular processes per se. The data were consistent with an effect of dexamethasone on thyroid stimulator. The putative stimulator does not appear to be normal pituitary thyrotropin (TSH), since TSH was not detected in serum of anyof the patients studied. Additionally, the changes observed were too rapid to be explained by a steroid-induced fall in the level of a circulating IgG thyroid stimulator. The data are consistent with the possibility that there may be a non-TSH non-IgG thyroid stimulator in Graves' disease.