Pooled analysis of individual patient data was used to compare the antidepressant efficacy of agomelatine with that of selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs). We sought head-to-head, double-blind, randomized studies without a placebo arm using antidepressant doses in the licensed range and primary evaluation on the Hamilton scale (HAM-D(17)). Six studies were identified versus venlafaxine, sertraline, fluoxetine, paroxetine or escitalopram. Estimates of differences between treatments were calculated on parameters expressed as the last postbaseline value (6, 8 or 12 weeks). A total of 2034 patients were randomized (age 47.6 ± 14.9 years; 73% women; HAM-D(17) total score 26.9 ± 3.0). The full analysis set included 1997 patients (1001 agomelatine; 996 SSRI/SNRI). There was a significant difference between HAM-D(17) total scores, with a greater reduction with agomelatine than with SSRI/SNRI [E(SE), 0.86 (0.35), 95% confidence interval 0.18-1.53, P=0.013], and better rates of response on the HAM-D(17) (P=0.012) and the Clinical Global Impression-Improvement scales (P=0.032). Similar results were found in patients with severe depression. Agomelatine was associated with better tolerability than SSRI/SNRI. Agomelatine has favourable efficacy and tolerability versus a range of SSRIs and SNRIs - including agents considered to have superior efficacy - and may deserve benefit-risk analysis as a first-line treatment of major depressive disorder.