Purpose <p>This study aimed to compare the effects of a conventional nasal cannula (NC) and a Procedural Oxygen Mask™ (POM™) on oxygenation and airway interventions during sedated endoscopic retrograde cholangiopancreatography (ERCP) in the semi-prone position.</p> Methods <p>In this prospective, randomized, controlled trial, 150 patients undergoing ERCP were randomized to receive oxygen via either an NC or a POM™. The primary outcome was the incidence of hypoxemia and secondary outcomes included the incidence of severe and prolonged desaturation, the duration of hypoxemia, the number of hypoxemic episodes per patient, and the lowest recorded SpO₂, along with the incidence of airway interventions, the incidence of procedure-disrupting body motions, hemodynamic changes, and satisfaction scores from both gastroenterologists and patients.</p> Results <p>Hypoxemia occurred in 14 patients (18.7%) in the NC group and in 4 patients (5.3%) in the POM™ group, with a significant difference between groups (p = 0.024). The lowest recorded SpO₂ was found to differ significantly between the two groups (<i>p</i> &lt; 0.001). In the multiple logistic regression analysis, NC use (aOR = 9.675; 95% CI 2.263–41.372; <i>p</i> = 0.002), higher total propofol dose (aOR = 1.014; 95% CI 1.007–1.022; <i>p</i> &lt; 0.001), lower preoperative hemoglobin levels (aOR = 0.635; 95% CI 0.455–0.886; <i>p</i> = 0.007), and elevated direct bilirubin levels (aOR = 1.296; 95% CI 1.078–1.559; <i>p</i> = 0.006) were independently associated with an increased risk of hypoxemia.</p> Conclusions <p>The use of a POM™ during ERCP while the patient is in the semi-prone position under sedation significantly reduces the incidence of hypoxemia and may therefore contribute to improved oxygenation management. This finding suggests that a POM™ is a viable alternative to NC.</p> Trial Registration <p>The clinical trial was registered at <a href="https://www.clinicaltrials.gov/">https://www.clinicaltrials.gov/</a> (NCT06681558) on October 31, 2024.</p>