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Background and Purpose: Major adverse cardiac events(MACE) are prevalent in patients with locally advanced-non-small cell lung cancer(LA-NSCLC) following radiotherapy(RT). The CHyLL model, incorporating coronary heart disease( C HD), Hy pertension(HTN), L ogarithmic L ADV15 was developed and internally-validated to predict MACE among LA-NSCLC patients. We sought to externally validate CHyLL to predict MACE in an independent LA-NSCLC cohort., Patients and Methods: Patients with LA-NSCLC treated with RT were included. CHyLL score was calculated:5.51CHD + 1.28HTN + 1.48ln(LADV15 + 1)-1.36CHD*ln(LADV15 + 1). CHyLL performance in predicting MACE was assessed and compared to mean heart dose(MHD) using Cox-proportional hazard(PH) analyses and Harrel's concordance(C)-indices. MACE and overall survival(OS) among low-vs high-risk groups(CHyLL < 5 vs ≥ 5) were compared., Results: In the external validation cohort(N = 102), the median age was 71 years and 55% were females. Most(n = 74,73%), had clinical Stage III disease and 35(34%) underwent surgery. CHyLL demonstrated good MACE prediction with C-index of 0.73(95% Confidence Interval(CI):0.58-0.89), while MHD did not (C-index = 0.46 (95% CI:0.30-0.62)). Per CHyLL, 32(31%) and 70(69%) patients were considered low-and high-risk for MACE, respectively. CHyLL consistently identified lower MACE rates in the low-vs high-risk group(log-rank p = 0.108):0 vs 8%(12 months),5 vs 16%(24 months),5 vs 16%(36 months),and 5 vs 19%(48 months) post-RT. In the pooled internal and external validation cohort(N = 303), MACE rates in low-vs high-risk groups were statistically significantly different(log-rank p = 0.01):1 vs 6%(12 months),3 vs 12%(24 months),6 vs 19%(36 months),and 6 vs 21%(48 months)., Conclusions: CHyLL was externally validated and superior to MHD in predicting MACE. CHyLL has the potential to identify high-risk patients who may benefit from cardio-oncology optimization and to estimate personalized LADV15 constraints based on cardiac risk factors and acceptable MACE thresholds., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Dr Bitterman reported personal fees from Agios Pharmaceuticals outside the submitted work. Dr Nohria reported grants from Amgen Inc, Bristol Myers Squibb and personal fees from AstraZeneca, Bantam Pharmaceuticals, and Takeda Oncology outside the submitted work. Dr Hoffmann reported consulting fees from Abbott, Duke University (National Institutes of Health [NIH]), Recor Medical and grants on behalf of Kowa Company, MedImmune, HeartFlow, Duke University (Abbott), Oregon Health & Science University (American Hospital Association 13FTF16450001), Columbia University (NIH, 5R01-HL109711), NIH/National Heart, Lung, and Blood Institute [NHLBI] 5K24HL113128, NIH/NHLBI 5T32HL076136, and NIH/NHLBI 5U01HL123339 outside the submitted work. Salary and Equity Cleerly Inc. Consultant/Salary Clinical Cardiovascular Sciences, Boston; Stanford University; Dr Mak reported personal fees from AstraZeneca, Novartis, Sio Capital, Varian Medical Systems, grants and personal fees from ViewRay Inc, and personal fees from NewRT outside the submitted work. All remaining authors have declared no conflicts of interest. Dr Atkins reported personal fees from OncLive outside the submitted work., (© 2023 The Authors.)