ABSTRACT Pulmonary vein isolation (PVI) is the cornerstone of ablation strategies for atrial fibrillation (AF) and has been consistently effective in reducing arrhythmia recurrence. Nonetheless, PVI has a recognized and not insignificant rate of short- and long-term failure, often requires multiple procedures and is less effective for persistent AF. The mechanisms of AF are diverse, but increased efferent cardiac sympathetic nerve stimulation can contribute to the development and perpetuation of AF. Reduction in cardiac sympathetic input has been proposed as a logical adjunctive approach to PVI but its technical application via cardiac ablation has had only mixed or modest results. The therapeutic objective of reduced cardiac sympathetic stimulation can be potentially accomplished by renal artery denervation (RDN), a technique originally developed for the treatment of resistant hypertension. RDN’s potential for antiarrhythmic effect may be mediated by reduced central nervous sympathetic output and is exemplified by a decrease in whole-body norepinephrine spillover and muscle-sympathetic nerve activity. The recently completed randomized, multicenter, single-blind clinical trial, ERADICATE-AF, was published in JAMA and convincingly demonstrated that RDN plus PVI resulted in a relative 43% reduction (absolute change, 15%; P < 0.001) in recurrent incident AF during one year of follow-up. The trial enrolled > 300 patients with paroxysmal AF referred for ablation, all with poorly controlled hypertension despite medication. There was no difference in complications between the 2 groups. The trial results suggested that a strategy of reducing cardiac autonomic input is an effective antiarrhythmic approach. Until now, this approach has only been tested in patients with resistant and/or poorly controlled hypertension. We propose a multicenter, single-blinded, randomized clinical trial to Evaluate Renal Artery Denervation In Addition to Catheter Ablation to Eliminate Atrial Fibrillation (ERADICATE-AF II), to test the hypothesis that RDN in addition to PVI enhances long-term antiarrhythmic efficacy in comparison to PVI alone for patients with persistent AF with controlled hypertension or without hypertension. The trial will be advantaged by performing implantable loop recordings (ILR) in all patients, which will facilitate the calculation of AF burden, now recognized as a powerful predictor of clinical outcome. With successful completion of this pilot program, we hope to launch a large-scale trial with cardiovascular and death events as endpoints. The principal goal of this trial is to determine if adjunctive RDN results in reduced AF burden over time in comparison to patients who undergo only PVI. The secondary goals are to examine: procedural complication, postural blood pressure, and pressure control as assessed by 24-hour ambulatory monitors; autonomic nervous system effects; frequency of cardiovascular hospitalizations; return to persistent AF; need...