Agomelatine and vortioxetine are antidepressants with different mechanisms of action compared to other pharmaceutical treatment options. The objective of this present analysis is to determine the relative efficacy and acceptability of agomelatine (25-50 mg) compared to vortioxetine (10-15-20 mg) in adult patients with major depressive disorder. We performed an adjusted indirect comparison using placebo as a common control. The main outcomes were efficacy (response to treatment by Montgomery-Åsberg depression rating scale/Hamilton Rating Scale for Depression) and acceptability (withdrawal rate for any reason or due to adverse events). 10 agomelatine and 11 vortioxetine studies were included in the analysis. For efficacy, no difference was shown between agomelatine and vortioxetine (E[95% CI] = -0.03 [-0.12;0.05]). For acceptability, no significant difference was found between both antidepressants. These findings substantiate current understanding that most antidepressants are of similar average efficacy and tolerability. Such equivalent therapeutic benefit of both compounds, measured by a quantitative clinical research approach, has to be discussed with the knowledge of a qualitative estimation in routine practice.