Background: Some patients fail to respond to persistent atrial fibrillation (PeAF) catheter ablation in spite of multiple procedures and ablation strategies, including low voltage area (LVA)-guided, linear, and complex fractionated atrial electrogram (CFAE)-guided ablation procedures. We hypothesized that LVA extent could predict non-responseto Pe AF catheter ablation in spite of multiple procedures. Methods: This study included 510 patients undergoing initial ablation procedures for PeAF. LVAs were defined as regions with bipolar peak-to-peak voltages of <0.50 mV after PVI during sinus rhythm. Patients were categorized by LVA size into groups A(0-5 cm2), B (5-20 cm2), and C (over 20 cm2). The primary endpoint was AF-free survival after the last procedure. Results: During a median follow-up of 25 (17, 36) months, AF recurrence was observed in 101 (20%) patients after 1.4±0.6 ablation procedures (maximum 4). Comparison of clinical outcomes after multiple procedures in the three groups showed that the results depended on the extent of LVA. Multivariate analysis of AF-free survival after the last procedure showed that LVAs > 20 cm2 was an independent factor associated with AF recurrence after the final procedure(Hazard ratio, 7.94; 95% confidence interval, 2.91 to 21.67, P <0.001). Conclusions: Extensive LVA after initial PVI was associated with poor clinical benefit despite multiple catheter based ablations