Objective: We herein compared the performance of reusable and disposable colonoscopes in patients scheduled to undergo colonoscopy with a view of preventing patient cross-infection, protecting the safety of clinical medical staff, reducing the risk of infection, and minimizing the decontamination process, particularly during the coronavirus disease 2019 pandemic. Methods: We randomly divided patients meeting the enrollment criteria into reusable and disposable colonoscopy groups; the success rate of photographing customary anatomical sites with a non-inferiority margin of -8% was the primary endpoint. Secondary endpoints were the adenoma detection rate, operation time, endoscopic image quality score, endoscopic mucosal resection (EMR) success rate, and adverse events. Results: We recruited patients who were treated using reusable or disposable (n = 45, each) colonoscopes. Both groups had 100% success rate for capturing images of customary anatomical sites, with no between-group differences. The lower limit of 95% CI was -7.8654%, which was greater than the non-inferiority threshold of -8%. The disposable group had a significantly lower average image quality score (26.09plus-or-minus sign1.33 vs. 27.44plus-or-minus sign0.59, P < 0.001) than the reusable group. The groups did not significantly differ in maneuverability, safety, or device failure/defect rate. The en-bloc EMR success rate was 100% in both groups. EMR took significantly longer in the disposable group (466.18 splus-or-minus sign180.56 s vs. 206.32 splus-or-minus sign109.54 s, P < 0.001). The incidence of EMR-related bleeding and perforation did not significantly differ between the groups. Conclusions: Disposable colonoscope endoscopy is safe and feasible for endoscopy examinations and EMR.