Gastrointestinal endoscopy is the method of choice for the diagnosis and treatment of diseases of the esophagus, stomach, and colon. Moderate sedation is commonly used to sedate patients for endoscopic procedures. The objective of this study is to determine whether supplemental oxygen administered prior to and during moderate sedation decreases episodes of clinically significant oxygen desaturation in adults undergoing endoscopic procedures. Three hundred eighty-nine subjects participated in the study. Of these, 194 patients were assigned to the experimental group and 195 patients to the control group. Use of supplemental oxygen was the study intervention. At baseline, the two groups did not differ significantly with respect to age, gender, body mass index, ethnicity, type of procedure, American Society of Anesthesiologists score, and pulse or respiratory rate. Of the control group, 70.8% (138/195) of patients experienced a desaturation episode compared with 12.4% (24/194) of experimental patients (p < .00001). Patients receiving supplemental oxygen were 98% less likely to experience desaturation than the controls. The results of this study support the routine use of supplemental oxygen (2 liters/minute) during endoscopic procedures to prevent desaturation. On the basis of the study data, it is recommended that patients undergoing endoscopy with moderate sedation, who meet the inclusion and exclusion criteria of this study, receive supplemental oxygen (2 L/min). Routine incorporation of this recommendation in hospital policies will ensure that patients routinely receive this preventive measure: supplemental oxygen during moderate sedation and the occurrence of clinically significant desaturation during endoscopic procedures.