A claimed advantage of colonoscopy over sigmoidoscopy in colorectal cancer (CRC) screening is prevention of CRC not only in the distal colon and rectum but also in the proximal colon. We aimed to assess the association of screening colonoscopy use with overall and site-specific CRC incidence and associated mortality. Information on use of screening colonoscopy as well as potential confounding factors was obtained at baseline in 2000-2002, updated at 2-, 5-, 8-, and 17-year follow-up from 9,207 participants aged 50-75 years without history of CRC in a statewide cohort study in Saarland, Germany. Covariate-adjusted associations of screening colonoscopy with CRC incidence and mortality, which were obtained through record linkage with the Saarland Cancer Registry and mortality statistics up to 2018, were assessed by Cox proportional hazards models with time-varying exposure information. During a median follow-up of 17.2 years, 268 participants were diagnosed with CRC and 98 died from CRC. Screening colonoscopy was associated with strongly reduced CRC incidence (adjusted hazard ratio [aHR] 0.44, 95% confidence interval [CI] 0.33-0.57) and mortality (aHR 0.34, 95% CI 0.21-0.53), with stronger reduction for distal (aHRs 0.36, 95% CI 0.25-0.51, and 0.33, 95% CI 0.19-0.59, respectively) than for proximal cancer (aHRs 0.69, 95% CI 0.42-1.13, and 0.62, 95% CI 0.26-1.45, respectively). Nevertheless, strong reduction of mortality from proximal cancer was also observed within 10 years after screening colonoscopy (aHR 0.31, 95% CI 0.10-0.96). In this large prospective cohort study from Germany, screening colonoscopy was associated with strong reduction in CRC incidence and mortality.