Background: To our knowledge, there are few trials studying the effect of high-flow nasal cannula (HFNC) during deep sedation. Our hypothesis is that high-flow nasal cannula (HFNC) will prevent hypoxemia and desaturation as compared to low-flow nasal cannula (LFNC) during prolonged deep sedation in patients with atrial fibrillation undergoing radiofrequency catheter ablation (RFCA). Methods: A single-centre, randomised controlled trial with HFNC as the intervention and LFNC as the control group. A total of 94 adult patients per group undergoing elective radiofrequency atrial fibrillation catheter ablation under deep sedation. will be included. The primary outcome is the lowest oxygen saturation (SpO₂). Secondary outcomes are as follows: the duration of lowest SpO₂, cross over from oxygen therapy in both directions, incidence of SpO₂ below 90% > 60 seconds, adverse sedation events, adverse effects of HFNC, mean CO₂, peak CO₂ and patients experience with oxygen therapy. The study will take place during the 2-day admission period for RFCA. Patients can fill out their questionnaires in the first week after treatment. Discussion: HFNC is increasingly used as a technique for oxygen delivery in procedural sedation and analgesia. We hypothesise that HFNC is superior to the standard treatment LFNC in patients under deep sedation with respect to the incidence of desaturation. To our knowledge, there are no adequately powered clinical trial studies on the effects of HFNC in prolonged deep sedation. Trial registration: ClinicalTrials.gov NCT04842253. Registered on 04 April 2021