Plasma concentrations of cortisol and corticosteroid- binding globulin are elevated substantially in pregnancy; only the free cortisol fraction is biologically active. Previous suggestions that plasma free cortisol increased above nongravid levels in pregnancy were difficult to reconcile with the absence of manifestations of hypercortisolism. Furthermore, any such elevation should be associated with some alteration in the regulation of cortisol secretion. Therefore, the physiology of cortisol secretion was studied by measuring plasma cortisol at 20-min intervals for 24 h. Free cortisol levels were evaluated by determining the plasma free cortisol index and the rate of urinary cortisol excretion. Circadian cortisol patterns in pregnant and nonpregnant subjects were virtually identical, but total plasma cortisol was significantly higher in pregnancy. Calculated plasma biological half-lives and production rates of cortisol were increased significantly in gravidas (t1/2: pregnant, 104.6 min; nonpregnant, 69.5 min; daily production rate: pregnant, 28.0 mg; nonpregnant, 11.2 mg). Such increases should produce rises in plasma free cortisol, an assumption supported by finding elevations of the free cortisol index in gravidas at 0800 and 2400 h (pregnant, 14.9 ± 1.9 and 3.3 ± 0.2; nonpregnant, 4.0 ± 0.6 and 1.2 ± 0.3) and elevations of the 24-h urinary cortisol excretion rate. Normal circadian rhythmicity despite elevated free cortisol suggests that maternal hypothalamic-pituitary regulation is altered. Resetting of feedback and lack of manifestations of hypercortisolism could be explained by tissue refractoriness to the effects of cortisol in pregnancy. © 1980 by The Endocrine Society.