This multicenter longitudinal observational trial was designed to analyze the long-term outcome of patients with heart failure (HF) treated with cardiac resynchronization therapy (CRT) alone or with implantable cardioverter-defibrillator (ICD) backup in a daily practice scenario. It is unknown whether the magnitude of survival benefits conferred by CRT in a daily practice scenario is comparable to what has been observed in randomized controlled trials and whether this benefit is sustained over the long term. The outcome of 1,303 consecutive patients with ischemic or nonischemic cardiomyopathy on optimal pharmacologic therapy treated from August 1, 1995 to August 1, 2004 at 4 European centers with CRT alone (44%) or with ICD backup for symptomatic HF and prolonged QRS duration was assessed. Cumulative event-free survival was evaluated for a combined end point, defined as death from any cause, urgent transplantation, or implantation of a left ventricular assist device. The cumulative incidence of competing events, HF, sudden cardiac death, and noncardiac death, was also assessed. Event-free survival was similar across the different centers. At 1 and 5 years, cumulative event-free survivals were 92% (95% confidence interval [CI] 91 to 94) and 56% (95% CI 48 to 64), respectively. The cumulative incidence of HF deaths was 25.1% (95% CI 19 to 31.7), whereas that of sudden death was 9.5% (95% CI 5.1 to 15.7). Using multivariate analysis, CRT with an ICD backup was associated with a nonsignificant decrease in mortality by 20% (hazard ratio 0.83, 95% CI 0.58 to 1.17, p = 0.284), with a highly significant protective effect against sudden cardiac death (hazard ratio 0.04, 95% CI 0.04 to 0.28, p <0.002). In conclusion, patients with advanced HF and a wide QRS complex routinely treated with CRT have a favorable long-term outcome that was reproducible at different centers. The leading cause of death in these patients remained HF, and this mode of death was competing with other causes in determining outcome. Total mortality was 20% lower with ICD backup (95% CI 42% lower to 17% higher) due to a protective effect against sudden cardiac death.