Agomelatine is the first approved antidepressant that mediates its activity through the melatoninergic pathway rather than the monoaminergic system. This meta-analysis aims to summarize an up-to-date report on the efficacy of agomelatine in major depressive disorder. Archives of published results in PubMed, CINAHL, Cochrane Library, EMBASE and PsycINFO databases were searched for randomized double-blind trials comparing agomelatine against placebo or antidepressant in major depressive disorder. Change in severity of depression as a result of intervention was the main outcome measure. Data necessary to compute the standardized mean difference (SMD) of this outcome and additional sample parameters that were likely to influence the main outcome were extracted for each selected studies. Summary effect sizes of various groups and subgroups were computed from SMDs between agomelatine and control (placebo or antidepressants) arms. There were nine trials involving 3943 severe cases of depression on agomelatine (n=2390) and either placebo (n=689) or antidepressants (n=864). Agomelatine (n=1274) stood superior to placebo (n=689) by a small margin (SMD -0.26, p=3.48×10-11) and the superiority of agomelatine (n=834, dose ≥ 25 mg/d) over antidepressants (paroxetine, fluoxetine, sertraline, venlafaxine; n=864) was even smaller (SMD -0.11, p=0.02). Although there is evidence of the superiority of agomelatine over placebo and selected antidepressants, it is questionable whether the magnitude of effect size is clinically significant and sample characteristics are relevant to the general patient population with major depressive disorder.