The purpose of this study was to assess the role of increases in maternal plasma cortisol, within the range observed after stress, in the control of fetal ACTH responses to subsequent fetal stress. We infused cortisol or vehicle into the inferior venae cavae of pregnant ewes which, with their fetuses (120-130 days gestation), had been chronically catheterized. Five-hour maternal cortisol infusions produced increases in maternal plasma cortisol smaller in magnitude than those induced by hypoxia stress and resulted in physiological increases in fetal plasma cortisol. One hour after the end of the maternal cortisol infusion, fetal ACTH secretion was stimulated by infusion of sodium nitroprusside into the fetal inferior vena cava. After maternal cortisol infusion, the fetal ACTH and cortisol responses to fetal hypotension were inhibited. We conclude that increases in maternal cortisol alters the fetal ACTH response to stress.