Objective: To explore the influence of low-dose estrogen replacement therapy on the Kupperman score and levels of hormones in patients with perimenopausal syndrome (PMS). Methods: A total of 100 patients with PMS were enrolled and randomly divided into two groups: observation group (n=50) and control group (n=66). Control group was given oral administration of Medroxyprogesterone Acetate, 4 mg/d, while observation group, based on which, was treated with oral Estradiol Valerate Tablets, 0.65 mg/d. After three-month treatment, the uterine volume, endometrial thickness, Kupperman score, levels of hormones as well as adverse reactions were compared between two groups. Results: Kupperman score decreased significantly in two groups after treatment compared with treatment before (P<0.01), and was lower in observation group than in control group after treatment (P<0.01). After three-month treatment, the level of estrogen increased significantly compared with treatment before (P<0.01), and was higher in observation group than in control group (P<0.01). The levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) decreased significantly after treatment compared with treatment before (P<0.01), and both in observation group were lower than those in control group (P<0.01). There was no difference between two groups after treatment in terms of uterine volume, endometrial thickness and adverse reactions (P>0.05). Conclusion: Low-dose estrogen replacement therapy is effective in promoting the normalization of hormone secretion in the body, in significantly improving the clinical symptoms, as well as in reducing the occurrence of adverse reactions of patients with PMS.