This study was designed to test whether increases in plasma progesterone (P) reduce the efficacy of plasma cortisol (F) in inhibition of ACTH responses to stimuli. Five nonpregnant ewes were each infused with ethanol-saline vehicle, F (4 micrograms/kg.min), P (0.5 or 2.0 microgram/kg.min), or P and F for 60 min. One hour after the end of the vehicle or steroid infusions, nitroprusside (20 micrograms/kg.min) was infused for 10 min to induce hypotension-stimulated ACTH secretion. Nitroprusside produced similar decreases in arterial blood pressure in all groups. Infusion of F alone inhibited plasma ACTH responses to hypotension. Whereas infusion of P without F did not significantly change plasma ACTH responses to hypotension, infusion of P with F caused greater ACTH responses to hypotension than did infusion of F alone. The results indicate that P can interfere with the delayed feedback effect of F in vivo.