In this 8-week double-blind multicenter trial, we evaluated the efficacy and safety of 2 fixed doses of agomelatine in patients with moderate to severe major depressive disorder. Primary efficacy variable was the change in 17-item Hamilton Depression Rating Scale (HAM-D17) total score from baseline to week 8/end of treatment. Secondary efficacy assessment compared the improvements in clinical response and remission (HAM-D17), Clinical Global Impression-Improvement Score, Clinical Global Impression-Severity Score, Hospital Anxiety and Depression (HAD), sleep (Leeds Sleep Evaluation Questionnaire), disability (Sheehan Disability Scale), and overall Quality of Life in Depression Scale between the agomelatine and placebo groups. Eligible patients (n = 511; baseline mean HAM-D17 score = 27.0) were randomized (1:1:1) to once-daily agomelatine, 25 mg; agomelatine, 50 mg; or placebo. Agomelatine 50 mg provided a statistically significant improvement in HAM-D17 score from first baseline visit through week 8 compared with placebo (week 8 treatment difference, 2.5; P = 0.004), whereas agomelatine 25 mg did not show (P = 0.505) a significant improvement. Treatment differences for all secondary efficacy variables were also statistically significant for agomelatine 50 mg versus placebo: Clinical Global Impression-Improvement (P = 0.012); Clinical Global Impression-Severity difference (P = 0.003); improvement in HAD total score, 2.2 (P = 0.014); patients' ability to get sleep (P < 0.001); quality of sleep (P = 0.002). Both doses of agomelatine were well tolerated relative to placebo. However, clinically notable transient aminotransferase elevations were observed in 4.5% of the patients in the agomelatine 50 mg group. The results showed significant antidepressant efficacy of agomelatine 50 mg/d, including a positive effect on sleep compared with placebo in outpatients with moderate to severe major depressive disorder.