BACKGROUND: Depression worsens the prognosis in patients with cardiac disease, and treatment with antidepressants may improve survival. Guidelines recommend use of selective serotonin reuptake inhibitors (SSRIs), but knowledge of the prognostic effect of different classes of antidepressants is sparse. METHODS AND RESULTS: We studied 99 335 patients surviving first hospitalization for heart failure (HF) from 1997 to 2005. Use of HF medication and antidepressants (divided into tricyclic antidepressants [TCA] and SSRI) was determined by prescription claims. Risk of overall and cardiovascular death associated with antidepressants, HF medication, and coadministration of these 2 drug classes was estimated by Cox proportional hazard analyses. Propensity adjusted models were performed as sensitivity analysis. During the study period, there were 53 988 deaths, of which 83.0% were due to cardiovascular causes (median follow-up, 1.9 years; 5, 95% fractiles, 0.04 to 7.06 years). Use of beta-blockers was associated with decreased risk of cardiovascular death (hazard ratio [HR], 0.77; 95% CI, 0.75 to 0.79). Antidepressants were prescribed to 19 411 patients, and both TCA and SSRI were associated with increased risk of overall and cardiovascular death (TCA: HR, 1.33; CI, 1.26 to 1.40; and HR, 1.25; CI, 1.17 to 1.32; SSRI: HR, 1.37; CI, 1.34 to 1.40; and HR, 1.34; CI, 1.30 to 1.38, respectively). Coadministration of SSRI and beta-blockers was associated with a higher risk of overall and cardiovascular death compared with coadministration of beta-blockers and TCA (P for interaction <0.01). CONCLUSIONS: Use of antidepressants in patients with HF was associated with worse prognosis. Coadministration of SSRIs and beta-blockers was associated with increased risk of overall death and cardiovascular death compared with coadministration of TCAs and beta-blockers. To further clarify this, clinical trials testing the optimal antidepressant strategy in patients with HF are warranted.