STUDY OBJECTIVE: To determine if a nasal positive airway pressure (nasal CPAP) mask would decrease the number of hypoxemic events in obese and obstructive sleep apnea patients undergoing colonoscopy. DESIGN: Single-center prospective randomized controlled trial. SETTING: Tertiary academic center. PATIENTS: We enrolled 109 patients with diagnosis of obesity and/or obstructive sleep apnea scheduled to undergo colonoscopy under propofol general anesthesia without planned tracheal intubation. INTERVENTION: Patients were randomly allocated (1:1 ratio) to receive supplementary oxygen at a flow of 10 L/min, either through a nasal CPAP or a simple facemask. MEASUREMENTS: The primary endpoint was the difference in the mean percentage of time spent with oxygen saturation below 90% between the two groups. Secondary outcomes included the need for airway maneuvers/interventions, average SpO2 during the case, duration and severity of oxygen desaturation, incidence and duration of procedural interruptions, and satisfaction and tolerance scores. MAIN RESULTS: 54 were allocated to the simple face mask and 55 to the nasal CPAP mask arms, respectively. A total of 6 patients experienced a hypoxemic event. Among these patients, the difference in the percentage of time spent with oxygen saturation below 90% was not clinically relevant (p = 1.0). However, patients in the nasal CPAP group required less chin lift (20% vs. 42.6%; p = 0.01) and oral cannula insertion (12.7% vs.29.6%; p = 0.03). The percentage of patients with at least one airway maneuver was higher in the simple face mask arm (68.5% vs. 41.8%; p = 0.005). Patient tolerance to device score was lower in the nasal CPAP group (8.85 vs. 9.56; p = 0.003). CONCLUSIONS: A nasal CPAP did not prevent hypoxemia and should not be used routinely for colonoscopy in obese or OSA patients if a simple face mask is an alternative therapy. However, potential advantages of its use include fewer airway maneuvers or interventions, which may be desirable in certain clinical settings. TRIAL REGISTRATION: Clinicaltrials.gov, identifier: NCT05175573.