Background & Aims: Propofol is under evaluation as a sedative for endoscopic procedures. We compared nurse-administered propofol to midazolam plus fentanyl for outpatient colonoscopy. Methods: One hundred out-patients undergoing colonoscopy were randomized to receive propofol or midazolam plus fentanyl, administered by a registered nurse and supervised only by an endoscopist. Endpoints were patient satisfaction, procedure and recovery times, neuropsychologic function, and complications. Results: The mean dose of propofol administered was 277 mg; mean doses of midazolam and fentanyl were 7.2 mg and 117 mu g, respectively. Mean time to sedation was faster with propofol (2.1 vs. 6.1 min; P < 0.0001), and depth of sedation was greater (P < 0.0001). Patients receiving propofol reached full recovery sooner (16.5 vs. 27.5 min; P = 0.0001) and were discharged sooner (36.5 vs. 46.1 min; P = 0.01). After recovery, the propofol group scored better on tests reflective of learning, memory, working memory span, and mental speed. Six minor complications occurred in the propofol group: 4 episodes of hypotension, 1 episode of bradycardia, and 1 rash. Five complications occurred with the use of midazolam and fentanyl: one episode of oxygen desaturation requiring mask ventilation and 4 episodes of hypotension. Patients in the propofol vs. midazolam and fentanyl groups reported similar degrees of overall satisfaction using a 10-cm visual analog scale (9.3 vs. 9.4, P > 0.5). Conclusions: Nurse-administered propofol resulted in several advantages for outpatient colonoscopy compared with midazolam plus fentanyl, but did not improve patient satisfaction.