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Background: Urogenital atrophy is a common problem after menopause and quality of life in post-menopauseis seriously affected by the symptoms associated with vaginal atrophy. The aim of this study was to compare the effectiveness of the vaginal suppository of hyaluronic acid and vitamin E in atrophic vaginitis treatment. Materials and Methods: This randomized double-blind clinical trialwas carried out in Ahvaz (Iran) from August to December 2010. Forty postmenopausal women with symptoms of vaginal atrophy were randomly allocatedto two groups to take vaginal suppositories of either 5 mg hyaluronic acid sodium salt (n=20) or 1 mg vitamin E (n=20) for 8 weeks. The symptoms of vaginal atrophy were evaluated by a self-assessed 4-point scaleand the composite score was determined asnone, mild, moderate, and severe in four periods. Results: The results showed that the symptoms were relieved significantly in both groups (P<0.001).The relief of symptoms was significantly superior in the hyaluronic acid group compared with the vitamin E group (P<0.05). Conclusion: Although both hyaluronic acid and vitamin E relieved the vaginal symptoms, improvements were greater in the hyaluronic acid group. Therefore,hyaluronic acid vaginal suppository is suggested for women with vaginal atrophy who do not want to or cannot take local estrogen treatment.