The safest and most efficient method of sedation for outpatient colonoscopy remains unclear. This study aimed to compare the efficiency and safety of bolus administration of midazolam compared with titrated administration and propofol administration for patients undergoing outpatient colonoscopy. We randomly divided patients undergoing colonoscopy into the propofol group, bolus midazolam group, and titrated midazolam group. We compared total procedure time, induction time, recovery time, and discharge time among the 3 groups. We also compared patient satisfaction and the incidence of adverse events. In total, 267 patients (89 in each study group) were enrolled during the study period. Patients in the propofol group had a shorter total procedure time (39.5 vs 59.4 vs 58.1 minutes; P< .001), induction time (4.6 vs 6.3 vs 7.6 minutes; P< .001), recovery time (11.5 vs 29.5 vs 29.2 minutes; P< .001), and discharge time (20.6 vs 34.9 vs 34.7 minutes; P< .001) than patients in the bolus midazolam group and titrated midazolam group. Patients in the propofol group reported higher degrees of satisfaction than patients in the bolus or titrated midazolam plus meperidine groups (9.9 vs 9.6 vs 9.6 [P= .007] and 4.9 vs 4.7 vs 4.8 [P= .008], respectively). Adverse events were not significantly different between groups. In this randomized trial, propofol was superior to bolus or titrated midazolam in terms of endoscopy unit efficiency and patient satisfaction during outpatient colonoscopy. (Clinical trial registration number: KCT0002805.).