Background: To examine the predictive value of early response for final outcome of psychotherapy and combined therapy in major depression. Methods: Mild- to moderately depressed patients were treated with either Short-Term Psychodynamic Supportive Psychotherapy (SPSP) (N = 63) only, or combined with an antidepressant (N = 127). Early response was defined as a reduction of more than 25% on the HAM-D-17 after 2 months. Outcome was determined in terms of complete nonresponse and remission rates. Associations between early response and outcome were examined using logistic regression analysis. Results: In SPSP, early nonresponse was clearly related to final nonresponse (OR = 3.57). Nevertheless, remission was not predicted by early response, and 26% of the early nonresponders ultimately achieved remission. In combined therapy, both final nonresponse (OR 7.13) and remission (OR 3.66) were associated with early nonresponse. Limitations: In this study, SPSP was the only psychotherapy examined. The design did not provide feedback to the therapist of the independently measured depression score after two months. Conclusion: Although a number of early nonresponsive patients will achieve remission, this study points out that these patients are at risk factor for ultimate treatment failure. This could be an indication for clinicians to adapt their treatment strategy. © 2007 Elsevier B.V. All rights reserved.