The present study determined whether the reduction in serum progesterone (P4) concentrations which follows the administration of the antiestrogen ethamoxytriphetol [1-(rho-2-diethylaminoethoxyphenyl)1-phenyl-2-rho-methoxyphenyl ethanol (MER-25)] to pregnant baboons reflects a decline in placental and/or luteal function. Maternal saphenous venous blood was collected at 1- to 4-day intervals between day 70 of gestation and term in pregnant baboons. Four females received no other treatment, and eight females received MER-25 (15 mg/kg BW, orally) daily between day 130 of gestation and term. Four of the MER-25-treated baboons received no other treatment, and four had the corpus luteum of pregnancy surgically excised between days 104 and 118 of gestation. Serum P4 concentrations in the untreated baboons fluctuated, but no significant progressive rise or fall in P4 occurred. Administration of antiestrogen to intact pregnant baboons resulted in a 50% decline (P less than 0.001) in serum P4 concentrations from mean pretreatment values of 7.0-25.1 to 4.2-10.8 ng/ml thereafter. Although removal of the corpus luteum alone had no effect on serum P4, administration of MER-25 to luteectomized females resulted in an 80% decrease (P less than 0.001) in serum P4 concentrations from pretreatment means of 10.6-16.6 to 2.5-3.2 ng/ml thereafter. The results indicate that most or all of the P4 that remained in the peripheral circulation after MER-25 administration to intact pregnant baboons originated from the ovary, primarily the corpus luteum. Thus, the major site of action of antiestrogen in reducing P4 production during baboon pregnancy is on the placenta.