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Drugs used for sedation/analgesia during gastrointestinal (GI) endoscopy, including midazolam, fentanyl, and propofol, result in short-term, reversible decline in cognitive function. This prospective cohort trial aimed to identify the sedative/analgesic regimen associated with the least impairment of cognition at the time of discharge.Patients undergoing elective GI endoscopy were included. Patients investigated at the Prince of Wales Hospital, Sydney, received midazolam/fentanyl (M/F), whereas patients investigated at the Prince of Wales Private Hospital, Sydney, received midazolam/fentanyl/propofol (M/F/P) or midazolam/propofol (M/P). Patients underwent a computerized neurocognitive test, the CogState Brief Battery, before sedation and at discharge.Patients in the M/F group who received gastroscopy (n=22) were administered midazolam 3.36 mg (±0.79 mg) and fentanyl 61.36 μg (±16.77 μg), those who received colonoscopy (n=50) were administered midazolam 3.98 mg (±1.06 mg) and fentanyl 74.50 μg (±24.48 μg), and those who received gastroscopy/colonoscopy (n=28) were administered midazolam 4.82 mg (±1.41 mg) and fentanyl 94.64 μg (±24.35 μg). Patients in the M/F/P group who received colonoscopy (n=45) were administered midazolam 2.77 mg (±0.55 mg), fentanyl 45.11 μg (±25.78 μg), and propofol 148.64 mg (±57.65 mg), and those who received gastroscopy/colonoscopy (n=36) were administered midazolam 2.64 mg (±0.472 mg), fentanyl 35.28 μg (±19.16 μg), and propofol 168.06 mg (±60.75 mg). Nineteen patients in the M/P group who received gastroscopy (n=19) were administered midazolam 2.37 mg (±0.04 mg) and propofol 13.68 mg (±37.74 mg). Neurocognitive scores were significantly lower in the postprocedure test compared with baseline scores for detection, identification, and one card learning (P<0.001). Postprocedure detection test scores were significantly impaired in the M/F group compared with the M/F/P and M/P groups. Predictors of poorer neurocognitive function were midazolam dosage >3 mg (P<0.006) and fentanyl dosage >50 μg (P<0.009).The use of propofol in GI endoscopy allows for less exposure to midazolam and fentanyl and is associated with improved cognition at the time of discharge.