BACKGROUND Pulse oximetry measures arterial oxygen saturation (SpO2), not hypoventilation, which is directly reflected by increases in carbon dioxide tension. METHODS In the present study, transcutaneous carbon dioxide tension (PtcCO2) and SpO2 were measured during 101 endoscopic procedures selected for long duration or comorbid illnesses, and relationships between hypercapnia and hypoxemia were evaluated. Nasal oxygen was administered only for sustained desaturation (SpO2 < 90%). RESULTS Mean peak increase in PtcCO2 was significantly higher in patients requiring oxygen for sustained desaturation (16.3 mm Hg; range, 4-52) than in patients breathing room air who had transient or no desaturation (10.2 mm Hg [range, 3-19] and 5.1 mm Hg [range, 0-15]). If nasal oxygen corrected desaturation, even transient recurrence of desaturation indicated worsening CO2 retention, which preceded respiratory arrest in one patient. Independent predictors of hypercapnia were fentanyl and midazolam doses, oxygen requirement, and dementia. CONCLUSIONS Severe hypoventilation may occur during endoscopy, undetected by clinical observation or pulse oximetry, but only in sedated patients who require supplemental oxygen to maintain SpO2 above 90%. After oxygen supplementation corrects desaturation, recurrence of desaturation implies severe hypoventilation and warrants limitation of further sedation.