Objective: To compare the pharmacokinetics and pharmacodynamics of 100 mg/d, 200 mg/d, and 400 mg/d (200 mg two times per day) of P administered vaginally for 14 days to estrogen-primed postmenopausal women. Design: Randomized, open-label, three-way crossover study. Setting: Two university- based investigative sites. Patient(s): Twenty healthy postmenopausal women with histologically normal endometria. Intervention(s): Oral 17β-E2 was given each day of a 28-day cycle; a P vaginal suppository was inserted daily according to the randomization schedule during days 15-28 of each cycle; blood samples were collected; an endometrial biopsy was obtained on day 25; and patients were crossed over to the next treatment cycle after a washout period of at least 30 days. Main Outcome Measure(s): Mean P blood levels, endometrial dating/conversion. Result(s): There was good vaginal absorption of P for all dosages. Endometrial conversion occurred in all 200- and 400- mg/d P-dosed cycles, whereas the 100-mg/d dosage failed to convert primed endometria consistently. There also was a significantly increased tendency for earlier bleeding and spotting with the 100-mg/d dosage. Conclusion(s): Both the 200- and 400-mg/d dosage regimens consistently convert an estrogen- primed endometrium, and yield appropriate endometrial dating and bleeding patterns. However, the 400-mg/d dosage attains the highest sustained blood levels and may be the best dosage regimen for further study.