Background: Optimal treatment of patients with persistent atrial fibrillation (AF) and heart failure (HF) with reduced left ventricular ejection fraction (LVEF) and an indication for internal defibrillator therapy is controversial. Methods: Patients with persistent/longstanding persistent AF and LVEF ≤35% were randomly allocated to catheter ablation of AF or best medical therapy (BMT). The primary study end point was the absolute increase in LVEF from baseline at 1 year. Secondary end points included 6-minute walk test, quality-of-life, and NT-proBNP (N-terminal pro-brain natriuretic peptide). Pulmonary vein isolation was the primary ablation approach; BMT comprised rate or rhythm control. All patients were discharged after index hospitalization with a cardioverter-defibrillator or cardiac resynchronization therapy defibrillator implanted. The study was terminated early for futility. Results: Of 140 patients (65±8 years, 126 [90%] men) available for the end point analysis, 68 and 72 patients were assigned to ablation and BMT, respectively. At 1 year, LVEF had increased in ablation patients by 8.8% (95% CI, 5.8%-11.9%) and in BMT patients by 7.3% (4.3%-10.3%; P=0.36). Sinus rhythm was recorded on 12-lead electrocardiograms at 1 year in 61/83 ablation patients (73.5%) and 42/84 BMT patients (50%). Device-recorded AF burden at 1 year was 0% or maximally 5% of the time in 28/39 ablation patients (72%) and 16/36 BMT patients (44%). There was no difference in secondary end point outcome between ablation patients and BMT patients. Conclusions: The AMICA trial (Atrial Fibrillation Management in Congestive Heart Failure With Ablation) did not reveal any benefit of catheter ablation in patients with AF and advanced HF. This was mainly because of the fact that at 1 year, LVEF increased in ablation patients to a similar extent as in BMT patients. The effect of catheter ablation of AF in patients with HF may be affected by the extent of HF at baseline, with a rather limited ablation benefit in patients with seriously advanced HF. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00652522.