BACKGROUND Depression is a risk factor for mortality in patients with heart failure (HF), however, treating depression with antidepressant therapy does not seem to improve survival. We examined the prevalence of antidepressant use in HF patients, the correlates of antidepressant use subsequent to hospital discharge and the relation between antidepressant use, clinical depression and mortality in patients with HF. METHODS 121,252 HF patients surviving first hospitalization were stratified by antidepressant use and a diagnosis of clinical depression. RESULTS In total, 15.6% (19,348) received antidepressants at baseline, of which 86.7% (16,780) had no diagnosis of clinical depression. Female gender, older age, higher socio-economic status, more comorbidities, increased use of statins, spironolactone and aspirin, lower use of beta-blockers and ACE-inhibitors, greater HF severity and a diagnosis of clinical depression were independently associated with antidepressant use. Patients using no antidepressants with clinical depression and patients using antidepressants, with or without clinical depression, had a significantly higher risk for all-cause mortality (HR, 1.25; 95% CI, 1.15-1.36; HR, 1.24; 95% CI, 1.22-1.27; HR, 1.21; 95% CI, 1.16-1.27, respectively) and CV-mortality (HR: 1.17; 95% CI, 1.14-1.20, P<.001; HR: 1.20; 95% CI, 1.08-1.34, P<.001; HR: 1.21; 95% CI, 1.12-1.29, P<.001, respectively) as compared to patients not using antidepressants without depression in adjusted analysis. CONCLUSIONS Patients with HF taking antidepressants had an increased risk for all-cause and CV-mortality, irrespectively of having clinical depression. These results highlight the importance of further examining the antidepressant prescription pattern in patients with HF, as this may be crucial in understanding the antidepressant effects on cardiac function and mortality.