Limited evidence exists to guide the optimal frequency of repeat endoscopic examination for colorectal cancer screening after a negative colonoscopy. To determine the duration and magnitude of the risk of developing colorectal cancer following performance of a negative colonoscopy. Population-based retrospective analysis of individuals whose colonoscopy evaluations did not result in a diagnosis of colorectal neoplasia. Patients who had been evaluated between April 1, 1989, and December 31, 2003, were identified using Manitoba Health's physician billing claims database (N = 35 975). Standardized incidence ratios (SIRs) were calculated to compare colorectal cancer incidence in our cohort with colorectal cancer incidence in the provincial population. Stratified analysis was performed to determine the duration of the reduced risk. Patients with a history of colorectal cancer prior to the index colonoscopy, inflammatory bowel disease, resective colorectal surgery, and lower gastrointestinal endoscopy within the 5 years before the index colonoscopy were excluded. Cohort members were followed up from the time of the index colonoscopy until diagnosis of colorectal cancer, death, out-migration from Manitoba, or end of the study period on December 31, 2003. Incidence of colorectal cancer. A negative colonoscopy was associated with SIRs of 0.69 (95% confidence interval [CI], 0.59-0.81) at 6 months, 0.66 (95% CI, 0.56-0.78) at 1 year, 0.59 (95% CI, 0.48-0.72) at 2 years, 0.55 (95% CI, 0.41-0.73) at 5 years, and 0.28 (95% CI, 0.09-0.65) at 10 years. The proportion of colorectal cancer located in the right side of the colon was significantly higher in the colonoscopy cohort than the rate in the Manitoba population (47% vs 28%; P<.001). The risk of developing colorectal cancer remains decreased for more than 10 years following the performance of a negative colonoscopy. There is a need to improve the early detection rate of right-sided colorectal neoplasia in usual clinical practice.