Cysteamine depletes pituitary and plasma prolactin in rats. It acts through a nondopaminergic mechanism to alter both immunoactive and bioactive prolactin. The effect of cysteamine on prolactin secretion is reported in normal men. Six normal subjects received a control thyrotropin-releasing hormone (TRH) test at 0900 using 200 micrograms TRH intravenously; serum prolactin and TSH were measured at -10, 0, 10, 20, 30, 60, and 90 min after administration of TRH. Serum calcium and parathyroid hormones levels were measured at -10 min. Seven or more days later, they received cysteamine hydrochloride 15 mg/kg body weight orally every 6 hours for 5 doses. One hour after the last dose, the TRH test was repeated. Peak serum prolactin levels following TRH, prolactin levels at the 10-min time point, and total area from 0 to 30 min under the prolactin secretory curve were significantly decreased by cysteamine administration. TSH levels were unchanged. Serum calcium levels were significantly decreased by cysteamine administration, but parathyroid hormone levels were unchanged. It was concluded that cysteamine reduced TRH-stimulated prolactin secretion. Cysteamine also decreases serum calcium levels and suppresses the anticipated rise in serum parathyroid hormone levels. These effects on serum calcium and parathyroid hormone are similar to those previously shown for WR2721, another sulfhydryl compound. Cysteamine should be further considered as an alternative drug in the treatment of hyperprolactinemia and as a therapeutic agent for hypercalcemia.