Context: In patients with diabetes mellitus, depression is a prevalent and recurrent problem that adversely affects the medical prognosis. Objective: To determine whether maintenance therapy with sertraline hydrochloride prevents recurrence of major depression in patients with diabetes. Design: A randomized, double-blind, placebo-controlled, maintenance treatment trial. Patients who recovered from depression during open-label sertraline treatment continued to receive sertraline (n=79) or placebo (n=73) and were followed up for up to 52 weeks or until depression recurred. Setting: Outpatient clinics at Washington University, St Louis, Mo, the University of Washington, Seattle, and the University of Arizona, Tucson. Patients: One hundred fifty-two patients with diabetes (mean age, 52.8 years; 59.9% female; 82.9% with type 2 diabetes) who recovered from major depression (43.3% of those initially assigned) during 16 weeks of open-label treatment with sertraline (mean dose, 117.9 mg/d). Intervention: Sertraline continued at recovery dose or identical-appearing placebo. Main Outcome Measures: The primary outcome was length of time (measured as the number of days after randomization) to recurrence of major depression as defined in DSM-IV. The secondary outcome was glycemic control, which was assessed via serial determinations of glycosylated hemoglobin levels. Results: Sertraline conferred significantly greater prophylaxis against depression recurrence than did placebo (hazard ratio=0.51; 95% confidence interval, 0.31-0.85; P=.02). Elapsed time before major depression recurred in one third of the patients increased from 57 days in patients who received placebo to 226 days in patients treated with sertraline. Glycosylated hemoglobin levels decreased during the open treatment phase (mean±SD glycosylated hemoglobin level reduction, -0.4%±1.4%; P=.002). Glycosylated hemoglobin levels remained significantly lower than baseline during depression-free maintenance (P=.002) and did not differ between treatment groups (P=.90). Conclusions: In patients with diabetes, maintenance therapy with sertraline prolongs the depression-free interval following recovery from major depression. Depression recovery with sertraline as well as sustained remission with or without treatment are associated with improvements in glycosylated hemoglobin levels for at least 1 year.