IMPORTANCE Antidepressant medication (ADM) is efficacious in the treatment of depression, but not all patients achieve remission and fewer still achieve recovery with ADM alone. OBJECTIVE To determine the effects of combining cognitive therapy (CT) with ADM vs ADM alone on remission and recovery in major depressive disorder (MDD). Copyright 2014 American Medical Association. All rights reserved.DESIGN, SETTING, AND PARTICIPANTS A total of 452 adult outpatients with chronic or recurrent MDD participated in a trial conducted in research clinics at 3 university medical centers in the United States. The patients were randomly assigned to ADM treatment alone or CT combined with ADM treatment. Treatment was continued for up to 42 months until recovery was achieved.INTERVENTIONS Antidepressant medication with or without CT. MAIN OUTCOMES AND MEASURES Blind evaluations of recovery with a modified version of the 17-item Hamilton Rating Scale for Depression and the Longitudinal Interval Follow-up Evaluation.RESULTS Combined treatment enhanced the rate of recovery vs treatment with ADM alone (72.6%vs 62.5%; t451 = 2.45; P = .01; hazard ratio [HR], 1.33; 95%CI, 1.06-1.68; number needed to treat [NNT], 10; 95%CI, 5-72). This effect was conditioned on interactions with severity (t451 = 1.97; P = .05; NNT, 5) and chronicity (χ2 = 7.46; P = .02; NNT, 6) such that the advantage for combined treatment was limited to patients with severe, nonchronic MDD (81.3%vs 51.7%; n = 146; t145 = 3.96; P = .001; HR, 2.34; 95%CI, 1.54-3.57; NNT, 3; 95%CI, 2-5). Fewer patients dropped out of combined treatment vs ADM treatment alone (18.9%vs 26.8%; t451 = -2.04; P = .04; HR, 0.66; 95%CI, 0.45-0.98). Remission rates did not differ significantly either as a main effect of treatment or as an interaction with severity or chronicity. Patients with comorbid Axis II disorders took longer to recover than did patients without comorbid Axis II disorders regardless of the condition (P = .01). Patients who received combined treatment reported fewer serious adverse events than did patients who received ADMs alone (49 vs 71; P = .02), largely because they experienced less time in an MDD episode.CONCLUSIONS AND RELEVANCE Cognitive therapy combined with ADM treatment enhances the rates of recovery from MDD relative to ADMs alone, with the effect limited to patients with severe, nonchronic depression.TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00057577.