METHOD: 100 healthy perimenopausal women were recruited and randomly assigned to two groups, with 50 subjects in each group. In the control group, placebo was administrated daily for 3 cycles (4 weeks of treatment for 1 cycle and drug withdrawals for 1 week). The study group received 3 mg oral melatonin treatment daily in the same period of time. All subjects completed the study. We compared the uterine volume, endometrial thickness, LH (luteinizing hormone), FSH (follicle generating hormone), E2 (estradiol), and melatonin levels during daytime between the two groups before and after the study. Moreover, perimenopause syndrome, sleep, mood, and QoL were analyzed at the baseline and 3 cycles by the questionnaires of the Kupperman index, the Pittsburgh sleep quality index (PSQI), the Hamilton anxiety scale (HAMA), and the Hamilton depression scale (HAMD), as well as menopausal QoL (MENQOL), respectively. Any adverse reactions experienced by the subjects were also compared in the study. Finally, 91 participants (92%) completed the whole study, 47 and 44 in the study and control groups, respectively, and their data were considered in subsequent analyses. RESULTS: After therapy, the two groups were similar in the uterine volume and endometrial thickness. In contrast to the control group, the study group showed notably decreased LH and FSH levels. No notable difference was discovered in E2 and melatonin levels between the two groups in the study. Moreover, the study group exhibited a significantly lower score in the Kupperman index, PSQI, HAMA, HAMD, and MENQOL scale than the control group. Moreover, the two groups had no notable difference in adverse reactions. CONCLUSION: Melatonin was a useful treatment to relieve climacteric symptoms and improve sleep, mood, and life quality in perimenopausal women without obvious adverse reactions.