Purpose: The study was performed to evaluate the efficacy and safety of locally applied estradiol cream (LinoladiolR N)- on vaginal atrophy in postmenopausal women in fractionated use. Material and Methods: In a randomized, double- blind, placebo- controlled parallel group study, 48 postmenopausal women self- administered 2 g of the test preparation (= 200 μ g estradiol) for 4 weeks and placebo cream as well. In the first week, the creams were used thrice in 48- hour intervals. In the weeks 2- 4, the application intervals were 3 and 4 days, respectively (twice weekly). The primary endpoint was the change in the vaginal maturation index (VMI). Secondary endpoints were clinical improvement of atrophy, vaginal pH, and number of lactobacilli. For safety assessment the serum levels of E2, FSH, LH, and SHBG were determined. The thickness of the endometrium was controlled sonographically and unexpected events were monitored systematically. Results: The estradiol treatment resulted in an increase in the VMI from 24.47% on day 1 to 64.23% on day 31. This is an enhancement of 39.56% . Under placebo, the change in VMI amounted only 5.16% . The difference between active treatment and placebo is highly significant (p < 0.0001). The improvement of vaginal cytology was mostly due to an increase in the superficial cells and a concomitant decrease in the basal and parabasal cells. In parallel, the use of estradiol improved the clinical symptoms of atrophy markedly. The mean pH value diminished in the treatment group from pH 6.0 to pH 4.2, correlated with a high proliferation of lactobacilli. During local treatment, the mean E2 plasma level increased slightly from 6.4 pg/ml to 15.1 pg/ml on day 31. The levels of FSH, LH, and SHBG were not significantly changed. There was no relevant change in mean endometrium thickness. The tolerability of the creams was good; there were no severe unexpected events. Conclusion: The results indicate that the fractionated use of vaginal estradiol cream (Linoladiol. N) causes rapid and extensive improvement of vaginal atrophy. This method of treatment can be considered safe. Purpose: The study was performed to evaluate the efficacy and safety of locally applied estradiol cream (Linoladiol NR) - on vaginal atrophy in postmenopausal women in fractionated use. Material and Methods: In a randomized, double-blind, placebo-controlled parallel group study , 48 postmenopausal women administered 2 g of the test preparation (= 200 μg estradiol) for 4 weeks and placebo cream as well. In the first week, the creams were used thrice in 48- hour intervals. In the weeks 2- 4, the application intervals were 3 and 4 days, respectively (twice weekly). The primary endpoint was the change in the vaginal maturation index (VMI). Secondary endpoints were clinical improvement of atrophy, vaginal pH, and number of lactobacilli. For safety assessment the serum levels of E2, FSH, LH, and SHBG were determined. The thickness of the endometrium was controlled sonographically and unexpected events were monitored systematically. Results: The estradiol treatment resulted in an incr ease in the VMI from 24.47% on day 1 to 64.23% on day 31. This is an enhancement of 39.56%. Under placebo, the change in VMI was only 5.16%. The difference between active treatment and placebo is highly significant (p < 0.0001). The improvement of vaginal cytology was mostly due to an increase in the superficial cells and a concomitant decrease in the basal and parabasal cells. In parallel, the use of estradiol improved the clinical symptoms of atrophy markedly. The mean pH value diminished in the treatment group from pH 6.0 to pH 4.2, correlated with a high proliferation of lactobacilli. During local treatment, the mean E2 plasma level increased slightly from 6.4 pg / ml to 15.1 pg / ml on day 31. The levels of FSH, LH, There was no relevant change in mean endometrium thickness. The tolerability of the creams was good; there were no severe unexpected events. Conclusion: The results indicate that the fractionated use of vaginal estradiol crea m(Linoladiol. N) causes rapid and extensive improvement of vaginal atrophy. This method of treatment can be considered safe.