Introduction: The long-term efficacy of high-power (50 W) ablation guided by lesion size index (LSI-guided HP) for pulmonary vein isolation (PVI) in patients with atrial fibrillation (AF) remains undetermined. Our study sought to assess the clinical efficacy of LSI-guided HP ablation for PVI in patients with AF and explore the potential predictors associated with clinical outcomes. Methods: We consecutively included 186 patients with AF who underwent LSI-guided HP (50 W) ablation at Fuwai Hospital from June 2019 to October 2021. The target LSI values of 4.5-5.5 and 4.0-4.5 at the anterior and posterior walls, respectively, were used in our study. The baseline clinical characteristics, procedural and ablation data, and clinical outcomes were evaluated. The independent potential predictors associated with AF recurrence were further evaluated. Results:The incidence rate of first-pass PVI was 83.9% (156/186). A total of 11 883 lesions were analyzed, and compared with posterior walls of pulmonary veins, anterior walls had significantly lower mean contact force (8.2 ± 3.0 vs. 8.3 ± 2.3 g, p = .015), longer mean radiofrequency duration (16.9 ± 7.2 vs. 12.9 ± 4.5 s, p < .001) and higher mean LSI (4.8 ± 0.2 vs. 4.4 ± 0.2, p < .001). The overall incidence of periprocedural complications was 3.7%, and steam pops without pericardial effusion occurred in three patients (1.6%). During a mean follow-up of 24.0 ± 8.4 months, the overall AF recurrence-free survival was 87.1% after a single procedure. Patients with paroxysmal AF had a higher incidence of freedom from AF recurrence than those with persistent AF (91.2% vs. 80.8%, log-rank p = .034). Higher LSI (HR 0.50, p < .001) and paroxysmal AF (HR 0.39, p = .029) were significantly associated with decreased AF recurrence. By receiver operating characteristic analysis, the LSI of 4.7 and 4.3 for the anterior and posterior walls of the PVs had the highest predictive value for AF recurrence, respectively. Conclusion: LSI-guided HP (50 W) ablation for PVI was an efficient and safe strategy and led to favorable single-procedure 2-year AF recurrence-free survival in patients with AF. Higher LSI and paroxysmal AF were independent predictors of decreased