The metabolic clearance rate (MCR) of progesterone was examined in the baboon to determine whether the increased serum progesterone concentrations during gestation result from increased production or decreased clearance. MCR was determined by constant infusion of [3H]progesterone in 6 non-pregnant baboons and 13 pregnant animals, between 58 and 175 days gestation. Progesterone MCR (mean+/-SE) was significantly greater in pregnant (1316+/-105 1/day, p less than 0.025; 87.3 +/- 6.2 1/day/kg, p less than 0.01) than in non-pregnant animals (893 +/- 75 1/day; 53.1 +/- 3.5 1/day/kg). There was no correlation between progesterone MCR and gestational age. Mean (+/- SE) progesterone MCR was similar during the follicular (938+/-119 1/day; 58.8+/-3.8 1/day/kg) and luteal (802+/-78 1/day; 52.4+/-6.8 1/day/kg) phases of the menstrual cycle. Serum progesterone concentrations (mean +/- SE, determined by radioimmunoassay, were 11.3+/-1.2 ng/ml in pregnant animals and 5.9+/-2.2 ng/ml during the luteal phase of the menstrual cycle. The mean (+/- SE) calculated progesterone production rates (MCR X serum progesterone concentration) were 4.57+/-1.74 mg/day during the luteal phase of the menstrual cycle and 15.26+/-2.48 mg/day during the last two-thirds of gestation. Thus, increased serum progesterone concentrations in pregnant baboons reflect enhanced production rather than decreased clearance. This is analogous to humans, but contrasts with rhesus monkeys, in which production is not increased during pregnancy. The elevated baboon progesterone MCR, despite increased serum corticosteroid binding capacity, indicates that other factors such as changes in maternal metabolism may also be important in regulating progesterone clearance.