Objectives: To compare the effects of a 12-week treatment with Pueraria mirifica (PM) gel or a conjugated estrogen cream on vaginal maturation index, vaginal symptom score, vaginal health assessment score, and vaginal flora in postmenopausal women. Methods: In a prospective, noninferiority, randomized controlled study, 82 postmenopausal women with at least one vulvovaginal symptom, that is, dryness, soreness, irritation, dyspareunia, or discharge, were recruited. Participants were randomly assigned into two groups for treatment with either PM gel or conjugated estrogen cream (CEE). The treatment regimen consisted of application of 0.5 g of product intravaginally daily for 2 weeks, and then decreased to three times per week for 10 weeks. Vaginal maturation index, vaginal symptoms score, and vaginal health assessment score were evaluated before the beginning of the study and at 6 weeks and 12 weeks after treatment with PM or CEE. Results: The vaginal maturation index increased significantly in both treatment groups at week 12, from 22.44 +/- 22.28 to 47.56 +/- 29.00 and from 27.07 +/- 26.12 to 66.90 +/- 22.42 in the PM and the CEE groups, respectively (P<0.05). A significantly higher effect was, however, observed in the CEE group (P<0.05). Vaginal symptom scores decreased significantly after treatment in both groups, from 4.37 +/- 2.79 to 0.95 +/- 1.88 and from 4.15 +/- 2.16 to 0.68 +/- 1.64 in the PM and the CEE groups, respectively (P0.05). Conclusions: The use of a 12-week treatment regimen with Pueraria mirifica gel was shown to be efficacious and safe for the treatment of vulvovaginal atrophy. Conjugated estrogen cream was found to be more effective compared to Pueraria mirifica gel in improving signs of vaginal atrophy and restoring vaginal epithelium at 6 and 12 weeks.