Fertile females of a New World primate species, the squirrel monkey (Saimiri sciureus), have plasma progesterone concentrations that vary between 57 and 510 ng/ml during the reproductive cycle and are 10- to 20-fold higher than those seen in cynomolgus monkeys (Macaca fascicularis) and other Old World primates, including man. The plasma progesterone level during pregnancy is high and varies between 140 and 490 ng/ml. Estradiol levels during the reproductive cycle and pregnancy are also higher than those of cynomolgus monkeys. After 2-day treatment of ovariectomized monkeys with estradiol in oil, the progesterone receptor content in the uterine cytosol of the squirrel monkey is one eighth that in similarly treated cynomolgus monkeys [60.4 +/- 6.5 fmol R5020 bound/mg protein vs. 496 +/- 55 (mean +/- SE); n = 8]. The receptor affinity for R5020 is the same in both species. Thus, the elevated plasma progesterone levels in squirrel monkeys appear to be a compensatory response to a receptor-mediated decrease in sensitivity to progesterone. The squirrel monkey may be a model for the study of the mechanism of action and regulation of secretion of progesterone.