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Purpose: The quality of life in postmenopause is seriously affected by the symptoms related to vaginal atrophy. To evaluate in a 3-month, prospective, randomized, double blind, study whether vaginal suppositories containing genistein might improve genital symptoms, colposcopical and cytologic findings or modify DNA cytometric features in postmenopausal women affected by vaginal atrophy, in comparison with vaginal suppositories containing hyaluronic acid (HA). Methods: A total of 62 postmenopausal women were randomly assigned to receive intravaginally 97 μg of genistein (group A, n = 31) or 5 mg of HA (group B, n = 31) daily for 15 days continuously/month for 3 months. Vaginal and cervical smear, colposcopy, vaginal biopsy were performed before and at the end of the study. Maturation value (MV) was calculated. Flow cytometric analysis of DNA ploidy (DI) and S-phase fraction (SPF) were performed. Results: After 90 days of study, a significant improvement was obtained in genital symptoms, colposcopy scores and MV ( p < 0.001) in both groups; the improvement obtained by genistein was more effective especially regarding genital score ( p value between groups 0.001). No significant change was found in SPF value and DI. Conclusion: Both treatments improved genital symptoms, colposcopical features and MV, although genistein was more effective on genital score. Both treatments did not significantly influence flow cytometry parameters, although genistein showed slight decrease in DI, with a normalization of the aneuploid content present in some cases that could represent an additional application of intravaginal phytoestrogen therapy, providing an alternative therapy of vaginal atrophy in postmenopausal patients. The results of this investigation should be considered preliminary and need to be verified in larger, prospective studies. [ABSTRACT FROM AUTHOR]