Population-based screening for colorectal cancer is an effective and cost-effective way of reducing colorectal cancer incidence and mortality. Many genetic and phenotypic risk factors for colorectal cancer have been identified, leading to development of colorectal cancer risk scores with varying discrimination. However, these are not currently used by population screening programs. We performed an economic analysis to assess the cost-effectiveness, clinical outcomes, and resource impact of using risk-stratification based on phenotypic and genetic risk, taking a UK National Health Service perspective. Biennial fecal immunochemical test (FIT), starting at an age determined through risk-assessment at age 40, was compared with FIT screening starting at a fixed age for all individuals. Compared with inviting everyone from age 60, using a risk score with area under the receiver operating characteristic curve of 0.721 to determine FIT screening start age, produces 418 QALYs, costs £247,000, and results in 218 fewer colorectal cancer cases and 156 fewer colorectal cancer deaths per 100,000 people, with similar FIT screening invites. There is 96% probability that risk-stratification is cost-effective, with net monetary benefit (based on £20,000 per QALY threshold) estimated at £8.1 million per 100,000 people. The maximum that could be spent on risk-assessment and still be cost-effective is £114 per person. Lower benefits are produced with lower discrimination risk scores, lower mean screening start age, or higher FIT thresholds. Risk-stratified screening benefits men more than women. Using risk to determine FIT screening start age could improve the clinical outcomes and cost effectiveness of colorectal cancer screening without using significant additional screening resources. PREVENTION RELEVANCE: Colorectal cancer screening is essential for early detection and prevention of colorectal cancer, but implementation is often limited by resource constraints. This work shows that risk-stratification using genetic and phenotypic risk could improve the effectiveness and cost-effectiveness of screening programs, without using substantially more screening resources than are currently available.