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Background: There is growing evidence for personalizing colorectal cancer screening based on risk factors. We compared the cost-effectiveness of personalized colorectal cancer screening based on polygenic risk and family history to uniform screening. Methods: Using the MISCAN-Colon model, we simulated a cohort of 100 million 40-year-olds, offering them uniform or personalized screening. Individuals were categorized based on polygenic risk and family history of colorectal cancer. We varied screening strategies by start age, interval and test and estimated costs, and quality-adjusted life years (QALY). In our analysis, we (i) assessed the cost-effectiveness of uniform screening;(ii) developed personalized screening scenarios based on optimal screening strategies by risk group; and (iii) compared the cost-effectiveness of both. Results: At a willingness-to-pay threshold of 50,000/QALY …