© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell. Background: Depression is a relapsing and remitting disease. Prior studies on the association between depressive symptoms and incident cardiovascular disease (CVD) have been limited by single measurements, and few if any have examined both incident coronary heart disease and stroke in a large biracial national cohort. We aimed to assess whether time-dependent depressive symptoms conferred increased risk of incident CVD. Methods and Results: Between 2003 to 2007, 22 666 black and white participants (aged ≥45 years) without baseline CVD in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study were recruited. Cox proportional hazards regression analyses assessed the association between up to 3 measurements of elevated depressive symptoms (4-item Center for Epidemiologic Studies Depression Scale score ≥4) and incident coronary heart disease, stroke, and CVD death adjusting for age, sex, region, income, health insurance, education, blood pressure, cholesterol, medication, obesity, diabetes mellitus, kidney disease, C-reactive protein, corrected QT interval, atrial fibrillation, left ventricular hypertrophy, smoking, alcohol, physical inactivity, medication adherence, and antidepressant use. The participants' average age was 63.4 years, 58.8% were female, and 41.7% black. Time-varying depressive symptoms were significantly associated with CVD death (adjusted hazard ratio 1.30, 95% CI 1.04-1.63), with a trend toward significance for fatal and nonfatal stroke (adjusted hazard ratio 1.26, 95% CI 0.99-1.60) but not fatal and nonfatal coronary heart disease (adjusted hazard ratio 1.11, 95% CI 0.89-1.38). Race did not moderate the association between depressive symptoms and CVD. Conclusions: Proximal depressive symptoms were associated with incident fatal and nonfatal stroke and CVD death even after controlling for multiple explanatory factors, further supporting the urgent need for timely management of depressive symptoms.