BACKGROUND: Conventional meta-analyses have shown inconsistent results for efficacy of second-generation antidepressants. We therefore did a multiple-treatments meta-analysis, which accounts for both direct and indirect comparisons, to assess the effects of 12 new-generation antidepressants on major depression. METHODS: We systematically reviewed 117 randomised controlled trials (25 928 participants) from 1991 up to Nov 30, 2007, which compared any of the following antidepressants at therapeutic dose range for the acute treatment of unipolar major depression in adults: bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, mirtazapine, paroxetine, reboxetine, sertraline, and venlafaxine. The main outcomes were the proportion of patients who responded to or dropped out of the allocated treatment. Analysis was done on an intention-to-treat basis. FINDINGS: Mirtazapine, escitalopram, venlafaxine, and sertraline were significantly more efficacious than duloxetine (odds ratios [OR] 1.39, 1.33, 1.30 and 1.27, respectively), fluoxetine (1.37, 1.32, 1.28, and 1.25, respectively), fluvoxamine (1.41, 1.35, 1.30, and 1.27, respectively), paroxetine (1.35, 1.30, 1.27, and 1.22, respectively), and reboxetine (2.03, 1.95, 1.89, and 1.85, respectively). Reboxetine was significantly less efficacious than all the other antidepressants tested. Escitalopram and sertraline showed the best profile of acceptability, leading to significantly fewer discontinuations than did duloxetine, fluvoxamine, paroxetine, reboxetine, and venlafaxine. INTERPRETATION: Clinically important differences exist between commonly prescribed antidepressants for both efficacy and acceptability in favour of escitalopram and sertraline. Sertraline might be the best choice when starting treatment for moderate to severe major depression in adults because it has the most favourable balance between benefits, acceptability, and acquisition cost.