Background: The TactiFlex™ ablation catheter, Sensor Enabled™ (Abbott, Minneapolis, MN, USA), is an open-irrigation radiofrequency (RF) ablation catheter with flexible tip technology. This catheter delivers high-power short-duration (HPSD) RF ablations and has been adopted for atrial fibrillation (AF) ablation. HPSD is well-established not only in pulmonary vein isolation (PVI) but also when targeting extra-pulmonary vein (PV) targets. This study aims to determine the safety, effectiveness, and acute outcomes of PVI plus posterior wall isolation (PWI) in patients with persistent atrial fibrillation (Pe-AF) using HPSD and the TactiFlex™ ablation catheter., Methods: Consecutive patients who underwent the ablation of Pe-AF in our centre between February 2023 and February 2024 were prospectively enrolled in the study. All patients underwent PVI plus PWI using TactiFlex™ and the HPSD strategy. The RF parameters were 50 W on all the PV segments and the roof, and within the posterior wall (PW). Left atrial mapping was performed with the EnSite X mapping system and the high-density multipolar Advisor HD Grid, Sensor Enabled™ mapping catheter. We compared the procedural data using HPSD with TactiFlex™ ( n = 52) vs. a historical cohort of patients who underwent PVI plus PWI using HPSD settings and the TactiCath ablation catheter ( n = 84)., Results: Fifty-two consecutive patients were included in the study. PVI and PWI were achieved in all patients in the TactiFlex™ group. First-pass PVI was achieved in 97.9% of PVs ( n = 195/199). PWI was obtained in all cases by delivering extensive RF lesions within the PW. There were no significant differences compared to the TactiCath group: first-pass PVI was achieved in 96.3% of PVs ( n = 319/331). Adenosine administration revealed PV reconnection in 5.7% of patients, and two reconnections of the PW were documented. Procedure and RF time were significantly shorter in the TactiFlex™ group compared to the TactiCath group, 73.1 ± 12.6 vs. 98.5 ± 16.3 min, and 11.3 ± 1.5 vs. 23.5 ± 3.6 min, respectively, p < 0.001. The fluoroscopy time was comparable between both groups. No intraprocedural and periprocedural complications related to the ablation catheter were observed. Patients had an implantable loop recorder before discharge. At the 6-month follow-up, 76.8% of patients remained free from atrial arrhythmia, with no significant differences between groups., Conclusions: HPSD PVI plus PWI using the TactiFlex™ ablation catheter is effective and safe. Compared to a control group, the use of TactiFlex™ to perform HPSD PVI plus PWI is associated with a similar effectiveness but with a significantly shorter procedural and RF time.