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Importance: Catheter ablation for persistent atrial fibrillation (AF) has shown limited success., Objective: To determine whether AF drivers could be accurately identified by periodicity and similarity (PRISM) mapping ablation results for persistent AF when added to pulmonary vein isolation (PVI)., Design, Setting, and Participants: This prospective randomized clinical trial was performed between June 1, 2019, and December 31, 2020, and included patients with persistent AF enrolled in 3 centers across Asia. Data were analyzed on October 1, 2022., Intervention: Patients were assigned to the PRISM-guided approach (group 1) or the conventional approach (group 2) at a 1:1 ratio., Main Outcomes and Measures: The primary outcome was freedom from AF or other atrial arrhythmia for longer than 30 seconds at 6 and 12 months., Results: A total of 170 patients (mean [SD] age, 62.0 [12.3] years; 136 men [80.0%]) were enrolled (85 patients in group 1 and 85 patients in group 2). More group 1 patients achieved freedom from AF at 12 months compared with group 2 patients (60 [70.6%] vs 40 [47.1%]). Multivariate analysis indicated that the PRISM-guided approach was associated with freedom from the recurrence of atrial arrhythmia (hazard ratio, 0.53 [95% CI, 0.33-0.85])., Conclusions and Relevance: The waveform similarity and recurrence pattern derived from high-density mapping might provide an improved guiding approach for ablation of persistent AF. Compared with the conventional procedure, this novel specific substrate ablation strategy reduced the frequency of recurrent AF and increased the likelihood of maintenance of sinus rhythm., Trial Registration: ClinicalTrials.gov Identifier: NCT05333952.