Background and Aims: Colorectal cancer (CRC) prevention by colonoscopy has been lower than expected. We studied CRC prevention outcomes of a colonoscopy protocol based on Clean the colon, Look Everywhere, and complete Abnormality Removal (CLEAR) principles. Methods: This observational follow-up study studied patients provided screening colonoscopy at a free-standing private ambulatory surgery center in South Carolina by 80 endoscopists from October 2001 to December 2014, followed through December 2015. The colonoscopy protocol, optimized for polyp clearance, featured in-person bowel preparation instructions reinforced by phone, polyp search and removal throughout insertion and gradual withdrawal with circumferential tip movements, and a team approach using all personnel present to maximize polyp detection, patient safety, and clear-margin polypectomy including requesting repeat inspection or additional tissue removal. Outcome measures were postscreening lifetime CRC risk relative to Surveillance Epidemiology and End Results (SEER)-18 and interval cancer rate (postcolonoscopy CRCs among cancer-free patients at screening). Results: Of 25,862 patients (mean age, 58.1 years; 52% black; 205,522 person-years of observation), 159 had CRC at screening and 67 patients developed interval CRC. The interval CRC rate was 3.34 per 10,000 person-years of observation, 5.79 and 2.24 among patients with and without adenomas, respectively. The rate was similar among older patients (mean age 68.5 years at screening) and with prolonged follow-up. Postscreening lifetime CRC risk was 1.6% (bootstrap 95% confidence interval, 1.3%-1.8%) versus 4.7% in SEER-18, 67% lower. Subgroups with mean screening ages of 50 and 68.5 years showed risk reductions of 80% and 72%, respectively. The adverse event rate was less than usually reported rates: perforation 2.6 per 10,000, bleeding with hospitalization 2.4 per 10,000, and no deaths. Conclusions: A colonoscopy protocol optimized for polyp clearance prevented 67% of CRC compared with a SEER-18 population given ongoing population screening.