BACKGROUND: Recent studies suggest that the use of antidepressants may be associated with increased mortality in patients with cardiac disease. Because depression has also been shown to be associated with increased mortality in these patients, it remains unclear if this association is attributable to the use of antidepressants or to depression. METHODS: To evaluate the association of long-term mortality with antidepressant use and depression, we studied 1006 patients aged 18 years or older with clinical heart failure and an ejection fraction of 35% or less (62% with ischemic disease) between March 1997 and June 2003. The patients were followed up for vital status annually thereafter. Depression status, which was assessed by the Beck Depression Inventory (BDI) scale and use of antidepressants, was prospectively collected. The main outcome of interest was long-term mortality. RESULTS: Of the study patients, 30.0% were depressed (defined by a BDI score > or =10) and 24.2% were taking antidepressants (79.6% of these patients were taking selective serotonin reuptake inhibitors [SSRIs] only). The vital status was obtained from all participants at an average follow-up of 972 (731) (mean [SD]) days. During this period, 42.7% of the participants died. Overall, the use of antidepressants (unadjusted hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.03-1.69) or SSRIs only (unadjusted HR, 1.32; 95% CI, 0.99-1.74) was associated with increased mortality. However, the association between antidepressant use (HR, 1.24; 95% CI, 0.94-1.64) and increased mortality no longer existed after depression and other confounders were controlled for. Nonetheless, depression remained associated with increased mortality (HR, 1.33; 95% CI, 1.07-1.66). Similarly, depression (HR, 1.34; 95% CI, 1.08-1.68) rather than SSRI use (HR, 1.10; 95% CI, 0.81-1.50) was independently associated with increased mortality after adjustment. CONCLUSION: Our findings suggest that depression (defined by a BDI score > or =10), but not antidepressant use, is associated with increased mortality in patients with heart failure.