Our objective was to investigate the first-pass effect to the uterus of progesterone gel administered vaginally. This was a prospective, randomized study of 32 postmenopausal women, attending our menopause clinic. All women used transdermal estradiol (50 microg/day, a patch each week) for 2 weeks. They used either vaginal progesterone gel or intramuscular progesterone in oil 50 mg after 24 h to oppose the transdermal estradiol. Serum progesterone levels and endometrial tissue progesterone levels were determined. Serum progesterone levels were higher in women who used the intramuscular rather than the vaginal route. Although serum progesterone levels in the vaginal group were lower than in the intramuscular group, the endometrial tissue concentration of progesterone was higher. It is concluded that progesterone gel, used vaginally, has a high local effect on the endometrium, without any systemic side-effects due to high plasma progesterone levels.