OBJECTIVE: To evaluate absorption of estradiol (E2) and compare two low doses of 17 beta-E2 (25 microgram and 10 microgram) in postmenopausal women with atrophic vaginitis. METHODS: In a double-masked, randomized, parallel-group study, 58 postmenopausal women were treated with 25 microgram or 10 microgram of 17 beta-E2 for 12 weeks. We report data for 42 eligible subjects who had serum E2 concentrations below 20 pg/mL at baseline and complete data available at the baseline visit (30 minutes before tablet insertion) and weeks 2 and 12. Serum E2 and FSH concentrations were measured at specified intervals. The area under the curve, maximal concentration, and time to maximal concentration were measured for serum E2 concentrations. Maturation values of vaginal epithelial cells were assessed as indicators of change in vaginal epithelium condition in response to treatment. RESULTS: After 12 weeks of treatment, the area under the curve, maximal and average over 24-hour E2 concentration were higher in the 25-microgram (563 pg. hour/mL, 49 and 23 pg/mL) than in the 10-microgram (264 pg. hour/mL, 22 and 11 pg/mL) group. Seventy-four percent in the 25-microgram and 96% in the 10-microgram groups had low systemic absorption of E2, that is, area under the curve (0-24 hour) less than 500 pg/mL. All but three women who received 25 microgram had mean FSH levels below 35 mIU/mL. CONCLUSION: Treatment with 25 or 10 microgram of 17 beta-E2 vaginal tablets resulted in low absorption of estrogen without systemic effects often associated with hormone replacement therapy. After 12 weeks of therapy for atrophic vaginitis, absorption patterns remained consistent, and women did not have accumulations of circulating E2.