Objective: The objective of this study was to evaluate the serum levels of progesterone resulting from the application of a progesterone cream to the skin. Study Design: Six postmenopausal women were evaluated at a university clinic over a 4-week period. Results: Transdermal estradiol 0.05 mg was applied 2 days before the first application of progesterone (30 mg/d) and was continued throughout the study. Patches were changed twice a week. Progesterone cream was applied once a day for 2 weeks. On day 15 and for the next 2 weeks, the progesterone cream was applied twice daily (60 mg/d). Serum 17β-estradiol and progesterone were measured at 9 different times over a 24-hour period on day 1 and at weekly intervals for the 4-week duration of the study. Serum 17β-estradiol concentrations varied among women, with mean concentrations of 40 to 64 pg/mL observed. Consistency in 17β-estradiol concentrations was found within individual persons throughout the study. Serum progesterone concentrations also varied among women, with mean concentrations ranging from 1.6 to 3.3 ng/mL. After 2 weeks of percutaneous dosing, progesterone concentrations were sustained for at least 8 hours and were consistent within a given person. An appropriate increase in progesterone concentration occurred after 4 weeks compared with 2 weeks of application. Individually, a 0.53 correlation, significant at P < .0001, was seen between the absorption of 17β-estradiol and progesterone. Conclusion: Significant increases in serum concentrations of progesterone were observed in all of the women studied. The percutaneous absorption of progesterone correlates strongly with the absorption of transdermal 17β-estradiol. There is variance in absorption of progesterone just as with 17β-estradiol, and the 2 measures are closely correlated. The percutaneous application of progesterone cream appears to be a safe and effective route of administration. (Am J Obstet Gynecol 1999;180:1504-11.)