Introduction Pulmonary vein isolation (PVI) using contact force (CF) sensing ablation catheters currently relies on CF and force-time integral (FTI) guidelines. Such measurement of lesion effectiveness still lacks information on current delivery to the tissue, influenced by system impedance and power. Lesion Index (LSI) is a multi-parametric index incorporating CF and radiofrequency current data across time. We aimed to prospectively assess safety and efficacy of an LSI-guided approach to PVI in patients with paroxysmal atrial fibrillation (PAF). Methods and results The study prospectively enrolled 28 consecutive patients with PAF undergoing PVI with a CF sensing catheter (TactiCathTM, Abbott). LSI-guided ablation target was adapted according to the mean regional thickness of pulmonary vein antra (PVA): LSI range 5.5-6 was pursued in the anterior and septal portions of PVA, 5-5.5 elsewhere. Data from 32 consecutive PAF patients who underwent PVI ablation with a non-CF guided approach (NCF-group) were retrospectively collected for comparison of procedural and clinical outcome. AF-free survival rate at follow-up (17±6 months) was higher for LSI-guided group than NCF-group (89.3% vs 65.6%, p=0.037), with no increase in periprocedural complication rate (no tamponades or other major adverse events reported). Among 1126 lesions with LSI within target range (5-6), average CF was >10g and <30g for 976 lesions (86.7%). Moreover, 1015 lesions (90.1%) had FTI>400gs, but with wide distribution: 30.2% within 400-500gs, 30.0% within 501-600gs, 29.9% over 600gs. Conclusion In this first prospective study, LSI-guided PVI improved clinical outcome without any increase in complication rate when compared with standard, non-LSI-guided approach.