Background: Bucindolol is a genetically targeted β-blocker/mild vasodilator with the unique pharmacological properties of sympatholysis and ADRB1 Arg389 receptor inverse agonism. In the GENETIC-AF trial (Genotype-Directed Comparative Effectiveness Trial of Bucindolol and Toprol-XL for the Prevention of Symptomatic Atrial Fibrillation/Atrial Flutter in Patients With Heart Failure) conducted in a genetically defined heart failure population at high risk for recurrent atrial fibrillation (AF), similar results were observed for bucindolol and metoprolol succinate for the primary end point of time to first AF event; however, AF burden and other rhythm control measures were not analyzed. Methods: The prevalence of ECGs in normal sinus rhythm, AF interventions for rhythm control (cardioversion, ablation, and antiarrhythmic drugs) and biomarkers were evaluated in the overall population entering efficacy follow-up (N=257). AF burden was evaluated for 24 weeks in the device substudy (N=67). Results: In 257 patients with heart failure, the mean age was 65.6±10.0 years, 18% were female, mean left ventricular ejection fraction was 36%, and 51% had persistent AF. Cumulative 24-week AF burden was 24.4% (95% CI, 18.5–30.2) for bucindolol and 36.7% (95% CI, 30.0–43.5) for metoprolol (33% reduction, P <0.001). Daily AF burden at the end of follow-up was 15.1% (95% CI, 3.2–27.0) for bucindolol and 34.7% (95% CI, 17.9–51.2) for metoprolol (55% reduction, P <0.001). For the metoprolol and bucindolol respective groups, the prevalence of ECGs in normal sinus rhythm was 4.20 and 3.03 events per patient (39% increase in the bucindolol group, P <0.001), while the rate of AF interventions was 0.56 and 0.82 events per patient (32% reduction for bucindolol, P =0.011). Reductions in plasma norepinephrine ( P =0.038) and NT-proBNP (N-terminal pro B-type natriuretic peptide; P =0.009) were also observed with bucindolol compared with metoprolol. Conclusions: Compared with metoprolol, bucindolol reduced AF burden, improved maintenance of sinus rhythm, and lowered the need for additional rhythm control interventions in patients with heart failure and the ADRB1 Arg389Arg genotype. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01970501.