Abstract Background Uncertainty persists about the safety and efficacy of amiodarone for the management of heart failure. Methods and Results We randomized 3029 patients with chronic heart failure to receive carvedilol or metoprolol and followed patients for a median of 58 months. One hundred fifty-five of 1466 patients in New York Heart Association (NYHA) Class II and 209 of 1563 in Class III or IV received amiodarone at baseline. Persistence with amiodarone treatment was high and 66% received amiodarone after 4 years. During follow-up, 38.7% and 58.9% of patients receiving amiodarone in NYHA Classes II and III + IV died versus 26.2% and 43.3% not receiving amiodarone ( P < .001). This difference was maintained in multivariable analysis (hazard ratio HR 1.5, 95% confidence interval CI 1.2–1.7, P < .001). The difference was explained by an increased risk of death due to circulatory failure (HR 2.4, CI 1.9–3.1, P < .001) in patients receiving amiodarone. Sudden death was not different (HR 1.07, CI 0.8–1.4, P = .7). The increased risk was similar across NYHA classes with HR of 1.60 (CI 1.2–2.1, P < .001) in NYHA Class II versus 1.58 (CI 1.3–1.9, P < .001) in Classes III + IV. Conclusions Treatment with amiodarone was associated with an increased risk of death from circulatory failure independent of functional class.