Objective: Depression may be associated with increased mortality risk, but there are substantial limitations to existing studies assessing this relationship. We sought to overcome limitations of existing studies by conducting a large, national, longitudinal study to assess the impact of depression on all-cause and cause-specific risk of death. Methods: We used Cox regression models to estimate hazard ratios associated with baseline depression diagnosis (N = 849,474) and three-year mortality among 5,078,082 patients treated in Veterans Health Administration (VHA) settings in fiscal year (FY) 2006. Cause of death was obtained from the National Death Index (NDI). Results: Baseline depression was associated with 17% greater hazard of all-cause three-year mortality (95% CI hazard ratio [HR]: 1.15, 1.18) after adjusting for baseline patient demographic and clinical characteristics and VHA facility characteristics. Depression was associated with a higher hazard of three-year mortality from heart disease, respiratory illness, cerebrovascular disease, accidents, diabetes, nephritis, influenza, Alzheimer's disease, septicemia, suicide, Parkinson's disease, and hypertension. Depression was associated with a lower hazard of death from malignant neoplasm and liver disease. Depression was not associated with mortality due to assault. Conclusions: In addition to being associated with suicide and injury-related causes of death, depression is associated with increased risk of death from nearly all major medical causes, independent of multiple major risk factors. Findings highlight the need to better understand and prevent mortality seen with multiple medical disorders associated with depression. Published by Elsevier Inc.