Levomilnacipran (1S, 2R-milnacipran) is a potent and selective serotonin and norepinephrine reuptake inhibitor that is Food and Drug Administration approved for once-daily treatment of major depressive disorder in adults. Secondary and post-hoc analyses were carried out on data from a positive 10-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter, proof-of-concept trial (EudraCT Number: 2006-002404-34) on 75 or 100 mg/day levomilnacipran extended release (ER). Included outpatients (18–70 years) met the criteria for a major depressive episode. There was a statistically significant difference in favor of levomilnacipran ER versus placebo in change from baseline to week 10 on every Montgomery Åsberg Depression Rating Scale (MADRS) single item (mixed-effects model for repeated measures; P<0.05) and most Hamilton Depression Rating Scale (HAMD17) single items. Significantly more levomilnacipran ER versus placebo patients (P<0.05) achieved ‘complete’ (MADRS≤5; 24 vs. 10%) and ‘sustained’ (MADRS≤10 in Weeks 4–10; 16 vs. 10%) remission, Sheehan Disability Scale (SDS) response (total score≤12 and each item score≤4; 52 vs. 35%) and remission (total score≤6 and each item score≤2; 26 vs. 17%), and combined symptomatic (MADRS) and functional (SDS) remission (19 vs. 8%). Treatment effects of similar magnitude were observed in the severe depression subgroup (MADRS≥30). These results demonstrate the benefit of levomilnacipran ER over placebo for patients with symptomatic and functional impairment associated with major depressive disorder.