Adverse cardiovascular outcomes such as coronary artery disease (CAD) are the leading noncancer causes of morbidity and mortality among childhood cancer survivors.The aim of this study was to assess the role of a genome-wide polygenic score (GPS) for CAD, well validated in the general population, and its interplay with cancer-related risk factors among childhood cancer survivors.In a cohort study of 2,472 5-year childhood cancer survivors from the St. Jude Lifetime Cohort, the association between the GPS and the risk of CAD was performed using Cox regression models adjusted for age at cancer diagnosis, sex, cumulative dose of anthracyclines, and mean heart radiation dose.Among survivors of European ancestry, the GPS was significantly associated with the risk of CAD (HR per 1 SD of the GPS: 1.25; 95% CI: 1.04-1.49;Childhood cancer survivors are at risk for premature CAD. A GPS may help identify those who may benefit from targeted screening and personalized preventive interventions.