Current guidelines recommend a 10-year interval between screening colonoscopies, but evidence is limited. To assess the long-term risk for colorectal cancer (CRC) and death from CRC after a high- and low-quality single negative screening colonoscopy. Observational study. Polish Colonoscopy Screening Program. Average-risk individuals aged 50 to 66 years who had a single negative colonoscopy (no neoplastic findings). Standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) of CRC after high- and low-quality single negative screening colonoscopy. High-quality colonoscopy included a complete examination, with adequate bowel preparation, performed by endoscopists with an adenoma detection rate of 20% or greater. Among 165 887 individuals followed for up to 17.4 years, CRC incidence (0.28 95% CI, 0.25 to 0.30) and mortality (0.19 CI, 0.16 to 0.21) were 72% and 81% lower, respectively, than in the general population. High-quality examination resulted in 2-fold lower CRC incidence (SIR, 0.16 CI, 0.13 to 0.20) and mortality (SMR, 0.10 CI, 0.06 to 0.14) than low-quality examination (SIR, 0.32 CI, 0.29 to 0.35; SMR, 0.22 CI, 0.18 to 0.25). In multivariable analysis, the hazard ratios for CRC incidence after high-quality versus low-quality colonoscopy were 0.55 (CI, 0.35 to 0.86) for 0 to 5 years, 0.54 (CI, 0.38 to 0.77) for 5.1 to 10 years, and 0.46 (CI, 0.25 to 0.86) for 10 to 17.4 years. Only after high-quality colonoscopy did the SIR and SMR for 10.1 to 17.4 years of follow-up not differ compared with earlier observation periods. The general population was used as the comparison group. A single negative screening colonoscopy was associated with reduced CRC incidence and mortality for up to 17.4 years. Only high-quality colonoscopy yielded profound and stable reductions in CRC incidence and mortality throughout the entire follow-up. Polish Ministry of Health.