PurposeColonoscopy is often accompanied by short-term postoperative cognitive decline. We aimed to explore whether single-use alfentanil for patients undergoing elective colonoscopy could reduce cognitive impairment at discharge compared with propofol. Patients and methods172 adult patients undergoing elective colonoscopy were randomized to receive intravenous propofol at 2 mg/kg (group P) or alfentanil at 10 μg/kg (group A); 40 healthy volunteers were included in the blank group. Cognitive function was considered the primary outcome and was measured using five neuropsychological tests before sedation and discharge. The z-score method was used to determine cognitive dysfunction according to z-score >1.96 in two types of neuropsychological tests. Other outcomes included discharge time, vital signs, associated adverse events during colonoscopy, and the satisfaction level of patients and endoscopic physicians. Results164 patients (78 in group A and 86 in group P) completed the study protocol. At discharge, the incidence of cognitive dysfunction in group P was 23% and was significantly lower in the alfentanil group (2.5%), with a relative risk of 0.11 (95% confidence interval: 0.03–0.46, P < 0.001). The incidence of hypotension in group A was lower than that in group P (3.8% vs 22.1%, relative risk = 0.17 [95% confidence interval: 0.05–0.46, P = 0.001]), and the discharge time in group A was shorter than that in group P (5 [3–9] vs 13 [10–18] min, P < 0.001). ConclusionFor patients undergoing colonoscopy, single-use alfentanil causes less damage to postoperative cognitive function, less risk of hypotension, and shorter discharge time than propofol.