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 [(Rutter and et al., 2016; Zhang and et al., 2013; Hirsh and et al., 2006; Zhou and et al., 2021; Singh and et al., 2008; Ko and et al., 2010; Sargin et al., 2019) 3–93–9 vs 13 [(Ekmekci and et al., 2017; Eberl and et al., 2012; Eberl and et al., 2014; N'Kaoua and et al., 2002; Chung et al., 1995; Berger and et al., 2019; Quan and et al., 2019; Deng and et al., 2021; Gualtieri and Johnson, 2006) 10–1810–18 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.