Genitourinary syndrome occurs due to a decrease in ovarian hormones; this can have a significant negative impact on women's interpersonal relationships and sexual function. The present study aimed at comparing the therapeutic effect of conjugated estrogens vaginal cream and a combined vaginal cream of vitamins D and E in the treatment of genitourinary syndrome in postmenopausal women. This study was conducted as a double-blind randomized clinical trial (RCT). As many as 64 postmenopausal women suffering from genitourinary syndrome were randomly divided into study and control groups. The study group was treated with a combined vaginal cream of vitamins D and E, and the control group was treated with conjugated estrogens vaginal creams for 12 weeks. The patients were visited at the beginning of being admitted, the fourth week, the 12th week, and four weeks after the treatment and their information was recorded by checklists and a sexual function questionnaire. The data were finally analyzed by SPSS-25 at a significant level of 0.05. At four visits, libido, orgasm, and frequency of sexual intercourses, as well as vaginal symptoms such as burning, itching, dryness, and dyspareunia were improved in both groups (P <.05). However, there was no difference between the two groups in terms of the frequency of severity of these symptoms during the four visits (P >.05). Investigating the female sexual function index showed that using vitamin D and E vaginal creams, like the use of conjugated estrogens vaginal creams, improves sexual function in women (P <.01). According to the results, it can be concluded that the combined vaginal cream of vitamins D and E is a suitable alternative to vaginal estrogens in relieving the symptoms of genitourinary syndrome in postmenopausal women, especially those who are unable to use hormone therapy or have little compatibility with this therapy.