The objective of this international, 8-week, randomized, double-blind study was to show the superiority of the antidepressant efficacy of agomelatine, the first MT1/MT2 receptor agonist and 5-HT2C receptor antagonist antidepressant, versus fluoxetine in outpatients fulfilling Diagnostic and Statistical Manual of Mental Disorders-volume IV-TR criteria for major depressive disorder of severe intensity, defined by a baseline Hamilton Depression Rating Scale (HAM-D17) total score of at least 25 and CGI severity of illness score of at least 4. Patients received agomelatine 25-50 mg/day (n=252) or fluoxetine 20-40 mg/day (n=263) for 8 weeks. The main efficacy outcome measure was HAM-D17 total score (change from baseline to last post-baseline assessment). Secondary outcome measures were Clinical Global Impressions-improvement (CGI), severity (CGI-S), anxiety (HAM-A), and sleep (HAM-D sleep items) scores. The mean decrease in HAM-D17 total score over 8 weeks was significantly greater with agomelatine than fluoxetine with a between-group difference of 1.49 (95% confidence interval, 0.20-2.77; P=0.024). The percentage of responders at last post-baseline assessment was higher with agomelatine on both HAM-D17 (decrease in total score from baseline ≥50%; 71.7% agomelatine vs. 63.8% fluoxetine; P=0.060) and CGI-improvement (score 1 or 2; 77.7 vs. 68.8%; P=0.023). There was a significant between-group difference of 0.37 (95% confidence interval, 0.06-0.68) in HAM-D sleep subscore in favor of agomelatine (P=0.018). Similar improvements were observed on HAM-A with agomelatine and fluoxetine. Both treatments were safe and well tolerated. In conclusion, in this study, agomelatine showed superior antidepressant efficacy over fluoxetine in treating patients with a severe episode of major depressive disorder after 8 weeks of treatment with a good tolerability profile.