Major depressive disorder (MDD) is associated with significant functional impairment. This post-hoc analysis of data from two randomized trials assessed the impact of response status on functioning in MDD. Patients with at least one historical treatment failure followed by an inadequate response after 8 weeks of prospective open-label treatment with escitalopram, fluoxetine, paroxetine-CR, sertraline, or venlafaxine-XR plus single-blind placebo were randomized to 6 weeks of double-blind treatment with adjunctive placebo or adjunctive aripiprazole. At the end of double-blind treatment, patients were defined as: in remission [>or=50% reduction in Montgomery-Asberg Depression Rating Scale (MADRS) score with MADRS <or=10]; with a response without remission (>or=50% reduction in MADRS with MADRS >10); or with a nonresponse (all others). Functional status was assessed with the Sheehan Disability Scale. Of the 679 patients, 144 were in remission, 44 had a response without remission, and 491 had a nonresponse. Mean improvements in the Sheehan Disability Scale total and item scores were significantly greater in patients in remission versus those with a response without remission (P<0.02) as well as nonresponse (P<0.001). Structural Equation Modeling found that efficacy (Hamilton Rating Scale for Depression scores) did not significantly correlate with functioning in this study. In conclusion, MDD patients achieving symptomatic remission experience greater functional improvements than those respond without remission. Functioning may be a distinctly different outcome from symptom reduction. Treatments focused on producing high remission rates may improve patient functioning over and above that seen with patients who only achieve response.