Background Electrical isolation of pulmonary veins (PV) with high-power short-duration (HPSD) radiofrequency application (RFa) may reduce the duration of atrial fibrillation (AF) ablation, without compromising the procedural efficacy and safety in comparison with the conventional approach. This hypothesis has been generated in several observational studies; the POWER FAST III will test it in a randomized multicenter clinical trial. Methods It is a multicenter randomized, open-label and non-inferiority clinical trial with two parallel groups. AF ablation using 70 W and 9–10 s RFa is compared with the conventional technique using 25–40 W RFa guided by numerical lesion indexes. The main efficacy objective is the incidence of atrial arrhythmia recurrences electrocardiographically documented during 1-year follow-up. The main safety objective is the incidence of endoscopically detected esophageal thermal lesions (EDEL). This trial includes a substudy of incidence of asymptomatic cerebral lesions detected by magnetic resonance imaging (MRI) after ablation . Results A randomized clinical trial compares for the first time high-power short-duration and conventional ablation in order to obtain data about the efficacy and safety of the high-power technique in an adequate methodological context. Conclusions The results of the POWER FAST III could support the use of the high-power short-duration ablation in clinical practice. Registration : ClinicalTrials.gov: NTC04153747. Graphical Abstract