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Background: Few studies have tested the effects of a depression intervention on the risk for death associated with depression. Objective: To test whether an intervention to improve depression care can modify the risk for death. Design: Practice-based, randomized, controlled trial. Setting: 20 primary care practices in New York, New York, and Philadelphia and Pittsburgh, Pennsylvania. Patients: 1226 randomly sampled patients identified through a 2-stage, age-stratified (60 to 74 years and [greater than or equal to] 75 years) depression screening. Intervention: Depression care manager working with primary care physicians to provide algorithm-based care. Measurements: Depression status based on clinical interview and vital status at 5 years by using the National Death Index. Results: At baseline, 396 patients met criteria for major depression and 203 patients met criteria for clinically significant minor depression. After a median follow-up of 52.8 months, 223 patients died. Patients with depression in intervention practices were less likely to have died than those in usual care practices (adjusted hazard ratio, 0.67 [95% Cl, 0.44 to 1.00]). Risk for death was reduced in patients with major depression (adjusted hazard ratio, 0.55 [Cl, 0.36 to 0.84]) but not in patients with clinically significant minor depression (adjusted hazard ratio, 0.97 [Cl, 0.49 to 1.92]). The benefit seemed to be almost entirely attributable to a reduction in deaths due to cancer. Limitations: The mechanism for an effect on deaths due to cancer is unclear. Depression status, cause of death, and vital status might have been misclassified. Conclusions: Older primary care patients with major depression in practices that implemented depression care management were less likely to die over a 5-year period than were patients with major depression in usual care practices. The effect seemed to be limited to deaths due to cancer. The mechanism for such an effect is unclear and warrants further investigation.