Background: Colonoscopy with a possible polypectomy is an efficient and preferred screening method to reduce the incidence of colorectal cancer (CRC). However, critics argue that, to date, a reduction of incidence and mortality from CRC has not been demonstrated in a population-based setting., Objective: To compare the incidence of and mortality from CRC among individuals screened by colonoscopy and non-screened individuals., Design: A closed cohort study., Setting: Population-based setting in a precisely defined area with a low level of population migration., Patients: This study involved 1912 screened and 20,774 control participants., Intervention: CRC cases in this closed cohort study were prospectively collected during the screening period of 1 year and the follow-up period of 6 years., Main Outcome Measurements: Follow-up data were corrected for negligible migration balance in the area. Tumor characteristics and risk or protective factors, age and sex, participation in general health screening examinations, history of CRC in a first-degree relative, smoking status, body mass index, frequency of sports activity, eating habits, and patients' professions were recorded., Results: Overall cancer incidence was significantly lower in the screened group compared with the non-screened group (adjusted odds ratio [OR] 0.31; 95% confidence interval [CI], 0.16-0.59; P < .001). Colon cancer-associated mortality also was clearly lower (adjusted OR 0.12; 95% CI, 0.01-0.93; P = .04). Risk factors such as lifestyle, smoking, and body mass index as well as family history were similar in both groups. Blue-collar workers had a higher incidence of CRC compared with professionals. The risk factors for CRC were a positive family history and smoking., Limitations: Number and ethnicity of the participants, non-randomized study., Conclusion: Colonoscopy with polypectomy significantly reduces CRC incidence and cancer-related mortality in the general population., (Copyright © 2012 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.)