Adrenocorticotropic hormone (ACTH) administration increases cortisol synthesis but produces a biphasic aldosterone response. Some investigators believe that the hypercortisolism from prolonged ACTH administration is responsible for this aldosterone response. The present study evaluated the plasma aldosterone response to four acute single-dose ACTH regimens that produced only a transient increase in plasma cortisol. Fourteen normal adult men received (1) 1-18 ACTH intravenous bolus (IV), (2) 1-18 ACTH intramuscular (IM), (3) 1-39 ACTH (IM), and (4) 1-24 ACTH (IV). The plasma aldosterone increased within one hour and tended to parallel the cortisol increment with all four ACTH regimens. With all of these ACTH regimens, the plasma aldosterone level decreased below placebo with 1-24 ACTH (IV) (24 hours), 1-39 ACTH (IM) (24 hours), and 1-18 ACTH (IV) and (IM) (48 hours) at a time when the cortisol had returned to normal. These results suggest that the delayed ACTH-induced aldosterone inhibition production are not directly related to cortisol production and do not require prolonged ACTH administration. These observations are consistent with ACTH induction of a nonaldosterone mineralocorticoid, which is independently suppressing aldosterone production.