It is commonly believed that the combination of antidepressant medications (ADM) and psychotherapy is more effective in the treatment of depression than is either treatment alone. There is evidence that adding cognitive therapy (CT) enhances the initial effects of ADM, but most of the relevant studies have suffered from low power. Moreover, findings from numerous studies suggest that CT has an enduring effect, but most of the evidence has been relevant to the prevention of relapse - the return of symptoms associated with the treated episode. There is little evidence on what is arguably the more critical prevention question: whether prior exposure to CT prevents recurrence - the onset of new episodes. What is needed is a study that is sensitive enough to detect the benefits that might accompany the addition of CT to ADM, and that can begin to address the attendant cost-effectiveness questions. The proposed design combines the goals and methods of efficacy and effectiveness research to these ends. We plan to randomly assign 450 depressed outpatients (150 at each of three sites) to ADM alone or to ADM plus CT. All patients will be treated to remission with a clinically representative ADM regimen, and half will, in addition, receive CT. Remitted patients will then be continued on medications for up to 12 months until they meet criteria for recovery, during which time CT will be continued as clinically indicated for patients in combined treatment. Once recovered, patients will be randomly assigned to either maintenance medications or medication withdrawal. Shortly thereafter, patients who have been receiving CT will be withdrawn from it as well. Patients will then be followed for a three-year period for the purpose of detecting recurrences. The main hypotheses are: (1) initial response will be better in ADM plus CT, relative to ADM alone; and (2) prior exposure to CT will protect against subsequent recurrence following medication withdrawal, to the same extent as maintenance ADM. Analyses will be employed to estimate the relative cost-effectiveness of adding CT to ADM for acute response and recurrence prevention.