To study the role of serotonin in regulating the release of aldosterone, we gave single, oral doses of cyproheptadine, an antiserotoninergic agent, to five normal volunteers with high aldosterone levels secondary to sodium deprivation and to 14 patients with aldosteronism (six with idiopathic aldosteronism due to bilateral adrenal hyperplasia and eight with adrenal adenoma). A diet containing 150 mmol of sodium was given to the patients with spontaneous aldosteronism, and one containing 10 mmol of sodium was given to the normal subjects, for three days before treatment and throughout the study. All subjects received dexamethasone, 2 mg daily. Serum aldosterone was measured with the subject in the recumbent position before cyproheptadine administration and at 30-minute intervals for two hours afterward. Serum aldosterone fell significantly (P less than 0.025) from the basal level in the patients with idiopathic aldosteronism due to hyperplasia. No fall was observed in the normal subjects or in the patients with adenoma. No changes were seen in renin activity, cortisol, sodium, or potassium, in any group after cyproheptadine. Suppression of aldosterone with cyproheptadine suggests a serotonin-mediated aldosterone-stimulating system. Hyperactivity of this system may be the cause of idiopathic aldosteronism associated with adrenal hyperplasia.