We conducted a retrospective cohort study to investigate the colorectal cancer (CRC) incidence and mortality prevention achievable in clinical practice with an optimized colonoscopy protocol targeting near-complete polyp clearance. The protocol consisted of: (i) telephonic reinforcement of bowel preparation instructions; (ii) active inspection for polyps throughout insertion and circumferential withdrawal; and (iii) timely updating of the protocol and documentation to incorporate the latest guidelines. Of 17,312 patients provided screening colonoscopies by 59 endoscopists in South Carolina, USA from September 2001 through December 2008, 997 were excluded using accepted exclusion criteria. Data on 16,315 patients were merged with the South Carolina Central Cancer Registry and Vital Records Registry data from January 1996 to December 2009 to identify incident CRC cases and deaths, incident lung cancers and brain cancer deaths (comparison control cancers). The standardized incidence ratios (SIR) and standardized mortality ratios (SMR) relative to South Carolina and US SEER-18 population rates were calculated. Over 78,375 person-years of observation, 18 patients developed CRC versus 104.11 expected for an SIR of 0.17, or 83% CRC protection, the rates being 68% and 91%, respectively among the adenoma- and adenoma-free subgroups (all p < 0.001). Restricting the cohort to ensure minimum 5-year follow-up (mean follow-up 6.64 years) did not change the results. The CRC mortality reduction was 89% (p < 0.001; four CRC deaths vs. 35.95 expected). The lung cancer SIR was 0.96 (p = 0.67), and brain cancer SMR was 0.92 (p = 0.35). Over 80% reduction in CRC incidence and mortality is achievable in routine practice by implementing key colonoscopy principles targeting near-complete polyp clearance.