Background: Investigators have shown that depression is associated with an increased risk of coronary heart disease in general and myocardial infarction in particular. However, it is unknown whether depression, independent of its association with myocardial infarction, is a risk factor for heart failure. Methods: This study examined whether depression was a predictor of incident heart failure among 4538 persons aged 60 years and older with isolated systolic hypertension who were enrolled in the Systolic Hypertension in the Elderly Program (SHEP). Depression was defined as a score of 16 or more at baseline on the Center for Epidemiological Studies Depression Scale (CES-D). The relationship between depression and heart failure was assessed using Cox proportional hazards regression. Results: The average follow-up was 4.5 years. Heart failure developed in 138 (3.2%) of 4317 nondepressed persons and in 18 (8.1%) of 221 depressed persons. After controlling for age; sex; race; history of myocardial infarction, diabetes, or angina; blood pressure; cholesterol levels; electrocardiographic abnormalities; smoking; disability; and SHEP treatment group, depressed persons had more than a 2-fold higher risk of developing heart failure compared with nondepressed persons (hazard ratio, 2.59; 95% confidence interval, 1.57-4.27; P<.001). After additional adjustment for the occurrence of myocardial infarction during follow-up, depressed persons remained at elevated risk of heart failure (hazard ratio, 2.82; 95% confidence interval, 1.714.67; P<.001). Conclusions: Depression is independently associated with a substantial increase in the risk of heart failure among older persons with isolated systolic hypertension. This association does not appear to be mediated by myocardial infarction.