BACKGROUND: Common sedation options for colonoscopy include propofol alone or a combination of midazolam and fentanyl. The former usually requires the presence of an anesthesia caregiver. The strategy that optimizes patient satisfaction has not yet been determined. OBJECTIVE: This study was designed to assess whether patient satisfaction at the time of colonoscopy is equivalent for propofol compared with midazolam and fentanyl. DESIGN: In this prospective, single-center, parallel group, single-blind, randomized, equivalence trial (NCT-01488045), 262 patients blinded to treatment received propofol (n = 126) or midazolam plus fentanyl (n = 136) at the time of colonoscopy. A patient satisfaction survey was administered in the recovery room and 1 to 5 days postprocedure. The endoscopist completed a survey immediately postprocedure. SETTINGS: This study was conducted at a tertiary academic hospital with a dedicated colon and rectal surgery division. PATIENTS: Patients over the age of 18 years who were undergoing elective colonoscopy were included in this study. MAIN OUTCOME MEASURES: The primary outcome was patient satisfaction with the colonoscopy. Secondary outcomes included physician and patient perception of patient pain, physician perception of patient tolerance of and difficulty of procedure, procedure duration, percentage of patients with cecal intubation, recovery time, and adverse events. RESULTS: Patient overall satisfaction scores in the recovery room after using the combination of midazolam and fentanyl (n = 136) during colonoscopy were not equivalent to patient satisfaction scores after using propofol (n = 126) alone (mean = 83.9 and 98.0 visual analog scale points) because the 90% CI (-18.5 to -9.6) for the mean treatment difference (-14.1) was completely outside the prespecified range of equivalence (±5 visual analog scale points). Patient pain as reported by the patient and as perceived by the physician and difficulty of the procedure were significantly worse for the midazolam/fentanyl group (n = 136) compared with the propofol group (n = 126). Time in the colonoscopy suite was significantly shorter for the propofol group, but the difference was small (4 minutes). There were no significant differences in percentage with cecal intubation, recovery time, or adverse events. LIMITATIONS: This is a single-institution, single-endoscopist study and is limited by the inability to perform blinding of the endoscopist. CONCLUSIONS: The use of propofol for conscious sedation during colonoscopy is associated with greater patient satisfaction and less pain when compared with midazolam/fentanyl, as perceived by the patient and endoscopist.