Intramuscular progesterone, 300–400 mg, was given daily to 5 normal men and to 2 hysterectomized women for 6 days to assess the role of this steroid in the development of hyperinsulinemia observed during pregnancy. Twentyfour hr urinary pregnanediol excretion increased to levels that were within the range of late gestation. On days 5 and 6 plasma glucose concentrations during oral glucose and intravenous tolbutamide tolerance tests were unchanged, but plasma insulin responses including fasting levels were significantly increased above control values. Patterns of insulin response were similar to those measured during studies of 10 normal women in late pregnancy. Progesterone effects were independent of any changes in fasting plasma glucose, free fatty acids, serum cortisol or immunoreactive growth hormone. These results suggest that progesterone, like pregnancy, evokes an enhanced plasma insulin response to insulinogenic stimuli as pancreatic islet adjustment to peripheral insulin antagonism evolves during gestation.