OBJECTIVE: The purpose of this study was to investigate whether the effects of 17beta-estradiol tablets that are designed for the treatment of postmenopausal urovaginal atrophy are influenced by the site of placement into the vagina. STUDY DESIGN: In this controlled crossover trial, 10 postmenopausal women received a single 17beta-estradiol tablet in the outer or inner one third of the vagina. Before and 3 hours after treatment, the pulsatility index, resistance index, and blood flow were evaluated in the uterine and periurethral vessels by Doppler examination. Parallel 17beta-estradiol serum evaluations were performed. RESULTS: Comparable and significant increases in 17beta-estradiol were observed. After inner administration, the pulsatility index and resistance index of both uterine arteries decreased; uterine artery blood flow increased significantly (P <.0001) but decreased in periurethral vessels (P <.02). After outer administration, the uterine artery pulsatility index, resistance index, and blood flow did not change, and the periurethral blood flow significantly increased (P <.0001). CONCLUSION: For optimizing the efficacy while minimizing the risk of endometrial hyperplasia, 17beta-estradiol tablets must be placed in the outer one third of the vagina.