Background: Several lines of evidence indicate that depression is importantly associated with cardiovascular disease end points. However, little is known about the role of depression in stroke mortality. Methods: This study examined the association between depressive symptoms and stroke mortality in a prospective study of behavioral, social, and psychological factors related to health and mortality in a community sample of 6676 initially stroke-free adults (45.8% male; 79.1% white; mean age at baseline, 43.4 years) from Alameda County, California. Depressive symptoms were assessed by the 18-item Human Population Laboratory Depression Scale. Cox proportional hazards regression models were used to evaluate the impact of depressive symptoms after controlling for age, sex, race, and other confounders. Results: A total of 169 stroke deaths occurred during 29 years of follow-up. Reporting 5 or more depressive symptoms at baseline was associated with increased risk of stroke mortality, after adjusting for age, sex, and race (hazard ratio, 1.66; 95% confidence interval, 1.16-2.39; P<.006). This association remained significant after additional adjustments for education, alcohol consumption, smoking, body mass index, hypertension, and diabetes (hazard ratio, 1.54; 95% confidence interval, 1.06-2.22; P<0.02). Time-dependent covariate models, which allowed changes in reported depressive symptoms and risk factor levels during follow-up, revealed the same pattern of associations. Conclusions: This population-based study provides the strongest epidemiological evidence to date for a significant relationship between depressive symptoms and stroke mortality. These results contribute to the growing literature on the adverse health effects of depression.