Patients with heart failure with reduced ejection fraction (HFrEF) derive less benefit from cardiac resynchronization therapy (CRT) if they have coexisting atrial fibrillation (AF). Observational data suggest that atrioventricular node ablation (AVNA) may enhance CRT efficacy in this population. This trial aimed to evaluate the effect of AVNA compared with medical rate control therapy (MRCT) on CRT outcomes in patients with HFrEF and permanent AF. The CAAN-AF trial was an international, prospective, multicentre, randomized controlled trial evaluating the impact of AVNA in patients with HFrEF, permanent AF, and CRT-defibrillators (CRT-D). Participants were randomly assigned (1:1) to AVNA or MRCT targeting a resting heart rate <90 bpm. All participants received device optimization. The primary endpoint was a composite of all-cause mortality and nonfatal heart failure events. Secondary endpoints included cardiovascular mortality, unplanned hospitalizations, ventricular arrhythmias requiring device therapy, 6-min walk distance (6MWD), and quality of life. With early termination of the trial due to futility, a total of 143 patients were randomized (67 to AVNA, 76 to MRCT). Baseline characteristics were similar across groups. No significant difference was found in the primary endpoint [47 vs. 46 events; incident rate ratio (IRR), 1.16; 95% confidence interval (CI), 0.60-2.24]. Secondary outcomes, including cardiovascular mortality (odds ratio, 1.93; 95% CI 0.60-6.20), unplanned hospitalizations (IRR, 1.01; 95% CI 0.71-1.74), ventricular arrhythmias requiring device therapy (IRR, 0.68; 95% CI 0.17-2.63), 6MWD, and SF-36 scores, also showed no significant differences. This randomized trial of patients with permanent AF and CRT-D found no evidence of a reduction in all-cause mortality and nonfatal heart failure events with AVNA compared with MRCT. NCT01522898.