BACKGROUND: Elderly patients with major depression, including those having a first episode, are at high risk for recurrence of depression, disability, and death. METHODS: We tested the efficacy of maintenance paroxetine and monthly interpersonal psychotherapy in patients 70 years of age or older who had depression (55 percent of whom were having a first episode) in a 2-by-2, randomized, double-blind, placebo-controlled trial. Among patients with a response to treatment with paroxetine and psychotherapy, 116 were randomly assigned to one of four maintenance-treatment programs (either paroxetine or placebo combined with either monthly psychotherapy or clinical-management sessions) for two years or until the recurrence of major depression. Clinical-management sessions, conducted by the same nurses, social workers, and psychologists who provided psychotherapy, involved discussion of symptoms. RESULTS: Major depression recurred within two years in 35 percent of the patients receiving paroxetine and psychotherapy, 37 percent of those receiving paroxetine and clinical-management sessions, 68 percent of those receiving placebo and psychotherapy, and 58 percent of those receiving placebo and clinical-management sessions (P = 0.02). After adjustment for the effect of psychotherapy, the relative risk of recurrence among those receiving placebo was 2.4 times (95 percent confidence interval, 1.4 to 4.2) that among those receiving paroxetine. The number of patients needed to be treated with paroxetine to prevent one recurrence was 4 (95 percent confidence interval, 2.3 to 10.9). Patients with fewer and less severe coexisting medical conditions (such as hypertension or cardiac disease) received greater benefit from paroxetine (P = 0.03 for the interaction between treatment with paroxetine and baseline severity of medical illness). CONCLUSIONS: Patients 70 years of age or older with major depression who had a response to initial treatment with paroxetine and psychotherapy were less likely to have recurrent depression if they received two years of maintenance therapy with paroxetine. Monthly maintenance psychotherapy did not prevent recurrent depression.