Administration of a large dose of ACTH caused an acute increase in aldosterone excretion in normal subjects, in cases of uncomplicated essential hypertension and in primary aldosteronism. Plasma renin levels were unaltered. The continued administration of ACTH for several days led to a fall in aldosterone excretion to below the control value in most cases, even when the subjects were maintained on a low salt diet. On the day after ceasing ACTH treatment, aldosterone transiently fell to even lower levels, which were also inappropriate to the low sodium intake. These various changes in aldosterone excretion produced by ACTH administration cannot be explained by any concurrent changes in activity of the renin-angiotensin system. The data also suggest that any changes in electrolyte metabolism induced by ACTH are only a minor influence in causing the depression in aldosterone secretion which follows its initial rise. This second part of the biphasic response therefore appears to result from a direct effect of either ACTH or released glucocorticoid on the adrenal cortex. In 4 of 5 cases of primary aldosteronism, aldosterone excretion also exhibited a biphasic response to ACTH, and it was further depressed to normal levels after stopping the drug. These latter results indicate that the adrenal adenoma typical of primary aldosteronism is not completely autonomous of humoral influences.