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Objectives: Chronic heart failure (HF) is associated with significantly increased prevalence of depression. The aim of the study was to assess the incidence and clinical impact of depression as well as the effectiveness of depression treatment in HF patients. Methods: A prospective interventional trial included 285 consecutive cardiac resynchronization therapy recipients. Patients underwent a psychiatric examination at the time of implantation and then it was routinely repeated at 3, 6, and 12 months after the procedure, and every 6 months thereafter. One hundred and thirty-five (47.4%) patients with depression were included in the depression group, whereas the control group was comprised of 150 patients free of depression. Sixty-eight (50.4%) subjects received antidepressants (treated group), whereas the observational group had 67 (49.6%) depressed patients who refused to take antidepressants. Results: Depression remission was achieved in 51 (75.0%) patients from the treated group. Long-term mortality and HF hospitalization rates were significantly higher in the depression group than in the control group (20.7 vs. 11.3% and 32.6 vs. 19.2%, respectively). However, remission from depression was associated with a 40% reduction in the relative risk of major adverse cardiac events (MACE). Conclusions: Patients with HF and concomitant depression are at higher risk of MACE compared with those free of depression. Effective antidepressant treatment may significantly improve long-term outcomes in this population.