This study assessed the efficacy of desvenlafaxine 50 mg/day compared with placebo for treating moderate or severe major depressive disorder (MDD). Data were pooled from six double-blind, placebo-controlled, desvenlafaxine 50 mg/day fixed-dose studies in adults with MDD. The primary endpoint was improvement in 17-item Hamilton Rating Scale for Depression (HAM-D17) scores from baseline at week 8. HAM-D17 changes were evaluated in patients with moderate (18<HAM-D17<25) or severe (HAM-D17≥25) MDD at baseline using analysis of covariance with treatment, study, and baseline in the model. The pooled analysis included 2189 patients (desvenlafaxine 50 mg, n=1150; placebo, n=1039). Of those, 694 (32%) patients had severe depression at baseline. Desvenlafaxine improved HAM-D17 scores versus placebo in patients with either moderate [desvenlafaxine, adjusted mean (±SE), −10.26±0.24; placebo, −8.87±0.26; P<0.001] or severe MDD (desvenlafaxine, −11.91±0.40; placebo, −9.85±0.42; P<0.001). Both moderately and severely depressed patients had significantly higher rates of response and remission with desvenlafaxine treatment compared with placebo (all P’s≤0.029). Results were similar when baseline severity was defined by Montgomery–Åsberg Depression Rating Scale or Sheehan Disability Scale scores. Desvenlafaxine 50 mg/day significantly improved depressive symptoms regardless of severity at baseline and was effective in treating both moderate and severe MDD.