Background: There is increasing interest in the use of propofol, an ultrashort-acting hypnotic agent, for sedation during endoscopic examinations. A protocol was developed for administration of propofol, combined with small doses of midazolam and meperidine, for endoscopic sedation under the direction of a gastroenterologist. Initial experience with using this protocol is described. Methods: A total of 819 consecutive endoscopic examinations under sedation with propofol, midazolam, and meperidine (or fentanyl), in adherence with the sedation protocol, were reviewed retrospectively. Results: There were 638 colonoscopies and 181 EGDs; 89% of patients were classified as American Society of Anesthesiologists (ASA) class I or II. Mean dosages of medications were: propofol 63 (33.5) mg, meperidine 48 (7.2) mg, and midazolam 1 (0.12) mg. The dose of propofol was inversely correlated with age and ASA class, and positively correlated with patient weight and duration of examination. Hypotension (>20 mm Hg decline in either systolic or diastolic blood pressure) developed in 218 (27%) patients, and hypoxemia (oxygen saturation <90%) developed in 75 (9%). All episodes of hypotension and hypoxemia were transient, and no patient required administration of a pharmacologic antagonist or assisted ventilation. The average time for recovery after colonoscopy and after EGD was, respectively, 25 minutes and 28 minutes. All EGDs and 98% of colonoscopies were completed successfully. Conclusions: On the basis of this initial experience, it is believed that propofol, potentiated by small doses of midazolam and meperidine, can be safely and effectively administered under the direction of a gastroenterologist. Additional research will be necessary to determine whether propofol is superior to the current methods of sedation.