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Vulvovaginal atrophy (VVA) is characterized by vaginal changes, dyspareunia, and itching/irritation. Efficacy and safety of a lower-dose estradiol vaginal cream (0.003%) were evaluated in postmenopausal women with VVA-related dyspareunia.This was a phase 3, randomized, double-blind, placebo-controlled study. Sexually active postmenopausal women with moderate–severe dyspareunia as the most bothersome symptom, ≤5% vaginal superficial cells, and vaginal pH >5.0 were randomized (1:1) to 0.003% estradiol vaginal cream (15 μg estradiol; 0.5 g cream) or placebo (0.5 g cream) applied daily for 2 weeks followed by three applications/week for 10 weeks. Coprimary outcomes were changes in dyspareunia severity, vaginal cytology, and vaginal pH from baseline to final assessment. Additional efficacy outcomes and safety were assessed.A total of 550 participants (average age, 58 y) were randomized. Compared with placebo, estradiol reduced dyspareunia severity (mean change from baseline ± SD: −1.5 ± 1.0 estradiol vs −1.2 ± 0.9 placebo), decreased vaginal pH (−1.36 ± 0.89 vs −0.53 ± 0.92), and improved vaginal cytology (percentage superficial and parabasal cells 10.1 ± 16.7 vs 1.4 ± 6.1 and −48.5 ± 45.1 vs −14.6 ± 39.6; P < 0.001, all) at the final assessment. In addition, estradiol decreased dyspareunia severity at weeks 8 and 12, vaginal/vulvar irritation/itching at weeks 4 and 12, and dryness at week 12 versus placebo (P < 0.01, all). VVA severity, pH, and cytology improved at week 12 with estradiol versus placebo (P < 0.001, all). Vulvovaginal mycotic infections were more frequent with estradiol. One serious event leading to discontinuation occurred with estradiol. No deaths occurred.Lower-dose estradiol vaginal cream (0.003%) dosed three applications/week is an effective and well-tolerated treatment for VVA-related dyspareunia.