IMPORTANCE Nearly half of postmenopausal women report bothersome vulvovaginal symptoms, but few data support the efficacy of 2 commonly recommended treatments. OBJECTIVE To compare the efficacy of a low-dose vaginal estradiol tablet and a vaginal moisturizer, each vs placebo, for treatment of moderate-to-severe postmenopausal vulvovaginal symptoms. DESIGN, SETTING, AND PARTICIPANTS This 12-week multicenter randomized clinical trial enrolled postmenopausal women with moderate to severe symptoms of vulvovaginal itching, pain, dryness, irritation, or pain with penetration. INTERVENTIONS Vaginal 10-μg estradiol tablet (daily for 2 weeks, then twice weekly) plus placebo gel (3 times a week) (n = 102) vs placebo tablet plus vaginal moisturizer (n = 100) vs dual placebo (n = 100). MAIN OUTCOMES AND MEASURES The main outcomewas decrease in severity (0-3) of most bothersome symptom (MBS) between enrollment and 12 weeks. Additional measures included a composite vaginal symptom score, Female Sexual Function Index (FSFI) score (2-36), modified Female Sexual Distress Score-Revised item 1, treatment satisfaction and meaningful benefit, Vaginal Maturation Index, and vaginal pH. RESULTS The 302 women had a mean (SD) age of 61 (4) years and were primarily white (267 [88%]), college educated (200 [66%]), and sexually active (245 [81%]). Most women (294 [97%]) provided data for the primary analysis. The most commonly reported MBS was pain with vaginal penetration (182 [60%]), followed by vulvovaginal dryness (63 [21%]). Mean baseline MBS severity was similar between treatment groups: estradiol, 2.4 (95%CI, 2.3 to 2.6); moisturizer, 2.5 (95%CI, 2.3 to 2.6); placebo, 2.5 (95%CI, 2.4 to 2.6). All treatment groups had similar mean reductions in MBS severity over 12 weeks: estradiol,-1.4 (95%CI,-1.6 to-1.2); moisturizer,-1.2 (95%CI,-1.4 to-1.0); and placebo,-1.3 (95%CI,-1.5 to-1.1). No significant differences were seen between estradiol (P = .25) or moisturizer (P = .31) compared with placebo. Mean total FSFI improvement was similar between estradiol (5.4; 95%CI, 4.0 to 6.9) and placebo (4.5; 95%CI, 2.8 to 6.1) (P = .64), and between moisturizer (3.1; 95%CI, 1.7 to 4.5) and placebo (P = .17). CONCLUSIONS AND RELEVANCE Our results suggest that neither prescribed vaginal estradiol tablet nor over-the-counter vaginal moisturizer provides additional benefit over placebo vaginal tablet and gel in reducing postmenopausal vulvovaginal symptoms.