BACKGROUND: Computer-aided detection (CADe) of colon polyps has been demonstrated to improve colon polyp and adenoma detection during colonoscopy by indicating the location of a given polyp on a parallel monitor. The aim of this study was to investigate whether embedding the CADe system into the primary colonoscopy monitor may serve to increase polyp and adenoma detection, without increasing physician fatigue level. METHODS: Consecutive patients presenting for colonoscopies were prospectively randomized to undergo routine colonoscopy with or without the assistance of a real-time polyp detection CADe system. Fatigue level was evaluated from score 0 to 10 by the performing endoscopists after each colonoscopy procedure. The main outcome was adenoma detection rate (ADR). RESULTS: Out of 790 patients analyzed, 397 were randomized to routine colonoscopy (control group), and 393 to a colonoscopy with computer-aided diagnosis (CADe group). The ADRs were 20.91% and 29.01%, respectively (OR = 1.546, 95% CI 1.116-2.141,  = 0.009). The average number of adenomas per colonoscopy (APC) was 0.29 and 0.48, respectively (Change Folds = 1.64, 95% CI 1.299-2.063,  < 0.001). The improvement in polyp detection was mainly due to increased detection of non-advanced diminutive adenomas, serrated adenoma and hyperplastic polyps. The fatigue score for each procedure was 3.28 3.40 for routine and CADe group,  = 0.357. CONCLUSIONS: A real-time CADe system employed on the primary endoscopy monitor may lead to improvements in ADR and polyp detection rate without increasing fatigue level during colonoscopy. The integration of a low-latency and high-performance CADe systems may serve as an effective quality assurance tool during colonoscopy. www.chictr.org.cn number, ChiCTR1800018058.