Background: To examine the association between the usage of agomelatine in patients with major depressive disorder and the usage of sedative-hypnotics. Methods: This population-based, cross-sectional study used Taiwan's National Health Insurance Research Database (NHIRD) between 2012 and 2015. The agomelatine-only group and matched control (1:3) with the usage of other antidepressants were enrolled. The association between the usage of the agomelatine and other antidepressants and the usage of sedative-hypnotics in the patients were also assessed. Results: A total of 7961 subjects were enrolled comprising 1985 with the usage of agomelatine only, and 5976 with other antidepressants. In the present study, a total of 3322 subjects who used the sedative-hypnotics were recorded, with 811 (40.86%) from the agomelatine-only group and 2511 (42.02%) from the non-agomelatine group, which have used sedativehypnotics. After adjusting for covariates, the odds ratio (OR) of the usage of sedativehypnotics in the agomelatine only-group was 0.892 (95% CI: 0.306-1.601, p = 0.533), in comparison to the controls, and the relative risk (RR) of the usage of sedative-hypnotics in the agomelatine only-group was 0.910 (95% CI: 0.312-1.633, p = 0.520), in comparison to the controls. No matter as to whether the treatment duration was <30 days or ≧ 30 days of agomelatine treatment was not associated with the increased usage of the sedative-hypnotics. The OR or RR for usage of the sedative-hypnotics was associated with the Charlson Comorbidity Index (CCI) scores as 2, 3, and ≧ 4, and the medical care from the medical center and regional hospital. Conclusion: Patients with the agomelatine-only group were not associated with the usage of sedative-hypnotics in comparison to the group using other antidepressants.