Major depressive disorder (MDD) is characterized by increased rates of impaired function and disability. During antidepressant treatment, functional improvement often lags behind symptomatic resolution, and residual impairment is associated with an increased risk for relapse. When evaluating MDD treatments, it is important to assess not only depressive symptoms but also functional outcomes. In this post-hoc analysis, data from five studies were pooled to examine the effect of levomilnacipran extended-release (ER) versus placebo on functional impairment as measured using the Sheehan Disability Scale. The mean change in the Sheehan Disability Scale total score was significantly greater for levomilnacipran ER versus placebo in the overall pooled population, for both sexes, and across all ages. Statistically significantly higher rates of functional response, functional remission, combined (functional and symptomatic) response, and combined remission were achieved with levomilnacipran ER compared with placebo in the pooled population, as well as in the male, female, younger, and middle-aged population subgroups. The levomilnacipran ER group also showed significantly improved functional outcomes versus placebo regardless of baseline depression severity. Similarly, functional impairment was significantly improved and higher functional and combined response and remission rates were achieved with levomilnacipran ER compared with placebo regardless of the baseline level of functional impairment.