The effect of large doses of glucocorticoids on thyrotropin (TSH) secretion in normal and hypothyroid humans has been studied. Plasma TSH concentrations were measured before, during, and after treatment with dexamethasone given orally for 24-48 hr. In 17 patients with primary hypothyroidism, plasma TSH levels fell significantly during treatment to a mean of 54% of control (range 23-96%). Within 48 hr after the withdrawal of dexamethasone, TSH concentrations transiently increased above pretreatment values. The mean increase was to 156% of control (range 106-294). Similar changes, but of smaller magnitude, were observed in 15 normal subjects. Administration of single oral doses of dexamethasone and oral or intravenous doses of cortisol were followed by reduction of plasma TSH levels to 18-47% of control within 8-12 hr in eight hypothyroid patients. This fall also was followed by significant TSH rises above control values before they returned to the pretreatment levels. Mineralocorticoid administration was not followed by any changes in plasma TSH concentrations in three subjects.TSH responses to steroid were also studied in rats. In hypothyroid rats given dexamethasone intravenously, plasma TSH fell to 63% of control in 30-90 min and then returned to normal or above in 3-4 hr. Dexamethasone also reduced plasma TSH concentrations in normal rats but no rebound was observed in these animals. Dexamethasone did not block the increase in plasma TSH produced by thyrotropin releasing factor (TRF) administration in vivo. Neither basal nor TRF-mediated TSH release from hemipituitaries in vitro was reduced by dexamethasone or corticosterone. These studies indicate that glucocorticoids reduce TSH secretion and suggest that this effect occurs at a suprahypophyseal level.