In randomized studies, the strategy of pulmonary vein (PV) antral isolation (PVI) plus linear ablation has failed to increase success rates for persistent atrial fibrillation (PeAF) ablation when compared with PVI alone. Peri-mitral reentry related atrial tachycardia due to incomplete linear block is an important cause of clinical failures of a first ablation procedure. Ethanol infusion (EI) into the vein of Marshall (EI-VOM) has been demonstrated to facilitate a durable mitral isthmus linear lesion. This trial is designed to compare arrhythmia-free survival between PVI and an ablation strategy termed upgraded '2C3L' for ablation of PeAF. The PROMPT-AF study is a prospective, multicenter, randomized trial involving blinded assessment of outcomes. Patients (n = 276) undergoing their first catheter ablation of PeAF will be randomized to either the upgraded '2C3L' arm or PVI arm in a 1:1 fashion. The upgraded '2C3L' technique is a fixed ablation approach consisting of EI-VOM, bilateral circumferential PVI and three linear ablation lesion sets across the mitral isthmus, left atrial roof, and cavo-tricuspid isthmus. The follow-up duration is 12 months. The primary endpoint is the rate of documented atrial tachycardia arrhythmias of >30 seconds, without any antiarrhythmic drugs, in 12 months after the index ablation procedure (excluding a blanking period of 3 months). The PROMPT-AF study will evaluate the efficacy of the fixed '2C3L' approach in conjunction with EI-VOM, compared with PVI alone, in patients with PeAF undergoing de novo ablation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.