BACKGROUND AND AIMS: Computer-aided detection (CADe) and a mucosal exposure device can improve adenoma detection rate (ADR). Potential benefits of combining the 2 modalities have never been studied. This study aimed to compare ADR differences among CADe alone, endocuff-assisted colonoscopy (EAC) alone, and the combination of CADe and EAC (CADe+EAC) with standard colonoscopy. METHODS: This prospective randomized controlled study included 1245 participants who underwent screening colonoscopy. Participants were randomized to CADe, EAC, CADe+EAC, and standard colonoscopy as a control. The primary outcome was ADR. Secondary outcomes were proximal ADR (pADR), advanced ADR (AADR), and the number of adenomas per colonoscopy (APCs). RESULTS: ADRs from the control, CADe, EAC, and CADe+EAC groups were 41.9%, 52.2%, 54.0%, and 58.8%, respectively; pADRs were 25.2%, 33.3%, 34.9%, and 37.0%, respectively; AADRs were 7.7%, 8.3%, 8.3%, and 13.6%, respectively; and APCs were .76, 1.11, 1.18, and 1.31, respectively. Significant increases in ADR and pADR were observed between the intervention and control groups (P < .05 in all comparisons). The AADR was significantly higher only in the CADe+EAC group than in the control group (P = .02). The adjusted incidence rate ratios of APCs were significantly higher in the intervention groups versus the control group (P < .01 in all comparisons). CONCLUSIONS: CADe+EAC significantly improve ADR and AADR over standard colonoscopy. However, although CADe or EAC alone can substantially increase the detection of adenomas, they do not lead to increased detection of advanced adenomas unless used in combination. (Clinical trial registration number: TCTR20200929003.).