Abstract Background Patients with multiple cardiovascular (CV) comorbidities are increasing users of health care globally. The decision to perform ablation of atrial fibrillation (AF) may be challenging in this population, due to the difficulty in evaluating their life expectancy and the associated procedural risk. In addition, no data have been reported on the efficiency, effectiveness, and safety outcomes for non-thermal ablation, such as electroporation with pulsed-field ablation (PFA). Purpose To evaluate procedural workflow and safety for AF ablation in these patients through a novel PFA technology (Farapulse) in a large, nationwide clinical practice. Methods Consecutive patients who had undergone PFA of AF from 10 Italian centers were included. Patients were stratified according to the numbers of several comorbidities, assigning 1 point each, including: advanced age (≥80 years), LVEF≤35%, structural heart disease, coronary artery disease, chronic kidney disease, chronic obstructive pulmonary disease, previous stroke/TIA, hyperthyroidism, cancer history, cancer ongoing, severe sleep apnea, diabetes, hypertension, dyslipidemia. Results We included 634 patients (age 62±9 years, 73% male, 67% paroxysmal AF, 88% de novo ablation procedure, LVEF 57±8%). Two-hundred-nine (33%) patients had no risk-factors, 179 (28.2%) patients had at least 1, 137 (21.6%) two, 63 (9.9%) patients 3 risk-factors and 46 (7.3%) patients more than 4 comorbidities. Patients with accumulated risk factors (≥4) had a higher percentage of long-standing AF (17.4% vs 5.4%, p=0.005) and more often underwent de novo ablation procedure (93.5% vs 81.3%, p=0.04). In these cases, operators decided to adopt more frequently, albeit not significantly, advanced diagnostic such as 3D mapping system (30.4% vs 21.9%, p=0.20) or intracardiac echocardiography (41.3% vs 29.8%, p=0.13), a general anesthesia sedation strategy (41.3% vs 32.1%, p=0.88) and a more extensive lesion set beyond PVI (i.e. left atrial posterior wall area, 32.6% vs 23.1%, p=0.15). Procedures in which patients with accumulated risk factors are involved required longer support (preparation plus skin-to-skin) time (90[65-120] min vs 72[60-100] min, p=0.02) and skin-to-skin time (70[60-100] min vs 60[55-85] min, p=0.03) compared to patients with <4 risk factors, whereas time to PVI (19[14-25] min vs 20[14-25] min, p=0.81) and total number of PFA deliveries to achieve PVI (32[32-38] vs 32[32-36], p=0.55) were similar. PVI was achieved in all patients. No major procedure-related adverse events were reported. Conclusion In this preliminary experience, the use of Farapulse PFA system for AF ablation in patients with accumulated risk factors was safe and effective and resulted in similar and fast time to PVI.