Objective: In a randomized clinical trial, we compared the efficacy of cognitive–behavioral therapy (CBT) and psychodynamic therapy for adult outpatient depression on measures of psychopathology, interpersonal functioning, pain, and quality of life. Method: There were 341 Dutch adults (70.1% female, mean age = 38.9, SD = 10.3) meeting Diagnostic and Statistical Manual for Mental Disorders-Fourth Edition (DSM–IV) criteria for a major depressive episode and with a Hamilton Depression Rating Scale (HAM-D) score ≥14, who were randomized to 16 sessions of individual manualized CBT or short-term psychodynamic supportive psychotherapy. Severely depressed patients (HAM-D >24) received additional antidepressant medication according to a protocol. Outcome measures included the Brief Symptom Inventory, Beck Anxiety Inventory, Outcome Questionnaire, a visual analogue scale for pain, and EuroQol. Data were analyzed with mixed model analyses using intention-to-treat samples. Noninferiority margins were prespecified as Cohen’s d = −0.30. Results: Across treatment conditions, 45–60% of the patients who completed posttreatment assessment showed clinically meaningful change for most outcome measures. We found no significant differences between the treatment conditions on any of the outcome measures at both posttreatment and follow-up. Noninferiority of psychodynamic therapy to CBT was shown for posttreatment and follow-up anxiety measures as well as for posttreatment pain and quality of life measures, but could not be consistently demonstrated for the other outcomes. Conclusions: This is the first study that shows that psychodynamic therapy can be at least as efficacious as CBT for depression on important aspects of patient functioning other than depressive symptom reduction. These findings extend the evidence-base of psychodynamic therapy for depression, but replication is needed by means of rigorously designed noninferiority trials.