OBJECTIVE: Agomelatine is a new antidepressant with unique melatonin receptor type 1A (MTNR1A) and 1B ( MTNR1B) agonism and serotonergic receptor 5-hydroxytryptamine receptor 2C (5-HT-2C) antagonism. Several studies of patients with major depressive disorder (MDD) have confirmed the superior efficacy and safety of agomelatine in comparison with established treatments, such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). This meta-analysis comprehensively shows the efficacy, acceptability, and safety of agomelatine in comparison with SSRIs and SNRIs used as antidepressants in MDD. METHOD: Comprehensive electronic database searches were performed to identify reports of head-to-head randomized controlled trials that have compared agomelatine with SSRIs or SNRIs in terms of efficacy/effectiveness in treating MDD. Response and remission rates at both acute (6-12 weeks) and follow-up (24 weeks) phases, Clinical Global Impression-Improvement Scale response and remission rates, changes in depression scale scores, improvements in subjective sleep, dropout rates, and side effect rates were extracted and analysed. RESULTS: The meta-analysis included six head-to-head trials involving 1871 patients. In the acute phase, agomelatine had higher response rates (relative risk (RR) 1.08, 95% confidence interval (CI) 1.02-1.15) compared to SSRIs and SNRIs. In the remission analysis, only acute remission rates (RR 1.12, 95% CI 1.01-1.24) significantly differed. The action of agomelatine was superior on the Leeds Sleep Evaluation Questionnaire-Quality of Sleep score (mean difference 4.05, 95% CI 0.61-7.49). Discontinuation due to inefficacy did not differ between agomelatine and SSRIs/SNRIs (RR 0.74, 95% CI 0.42-1.28). Compared to SSRIs and SNRIs, however, agomelatine revealed a lower rate of discontinuation due to side effects (RR 0.38, 95% CI 0.25-0.57). CONCLUSIONS: Agomelatine has significantly higher efficacy and potential acceptability compared to SSRIs and SNRIs when treating MDD. However, the difference in efficacy is not considered clinically relevant. Because of its unique chronobiotic effects, agomelatine may be useful for the management of some MDD patients with circadian disturbance.