Previous studies on the cost-effectiveness of personalized colorectal cancer (CRC) screening were based on hypothetical performance of CRC risk prediction and did not consider the association with competing causes of death. In this study, we estimated the cost-effectiveness of risk-stratified screening using real-world data for CRC risk and competing causes of death. Risk predictions for CRC and competing causes of death, from a large community-based cohort, were used to stratify individuals into risk groups. A microsimulation model was used to optimize colonoscopy screening for each risk group by varying the start age (40-60 years), end age (70-85 years), and screening interval (5-15 years). The outcomes included personalized screening ages and intervals, and cost-effectiveness compared to uniform colonoscopy screening (ages 45-75, every 10 years). Key assumptions were varied in sensitivity analyses. Risk-stratified screening resulted in substantially different screening recommendations, ranging from a one-time colonoscopy at age 60 for low-risk individuals to a colonoscopy every five years from ages 40-85 for high-risk individuals. Nevertheless, on a population-level, risk-stratified screening would increase net quality adjusted life years gained (QALYG) by only 0.7% at equal costs to uniform screening, or, reduce average costs by 1.2% for equal QALYG. The benefit of risk-stratified screening improved when it was assumed to increase participation or costs less per genetic test. Personalized screening for CRC, accounting for competing causes of death risk, could result in highly tailored individual screening programs. However, average improvements across the population in QALYG and cost-effectiveness compared with uniform screening are small.