BACKGROUND: Low-cost/no-cost non-contrast CT calcium scoring (CTCS) exams can provide direct evidence of coronary atherosclerosis. In this study, using features from CTCS images, we developed a novel machine learning model to predict obstructive coronary artery disease (CAD), as defined by the coronary artery disease-reporting and data system (CAD-RADS). METHODS: This study analyzed 1324 patients from the SCOT-HEART trial who underwent both CTCS and CT angiography. Obstructive CAD was defined as CAD-RADS 4A-5, while CAD-RADS 0-3 were considered non-obstructive CAD. We analyzed clinical, Agatston-score-derived, and epicardial fat-omics features to predict obstructive CAD. The most predictive features were selected using elastic net logistic regression and used to train a CatBoost model. Model performance was evaluated using 1000 repeated five-fold cross-validation and survival analyses to predict major adverse cardiovascular event (MACE) and revascularization. Generalizability was assessed using an external validation set of 2316 patients for survival predictions. RESULTS: Among the 1324 patients, obstructive CAD was identified in 334 patients (25.2 %). Elastic net regression identified the top 14 features (5 clinical, 2 Agatston-score-derived, and 7 fat-omics). The proposed method achieved excellent performance for classifying obstructive CAD, with an AUC of 90.1 ± 0.9 % and sensitivity/specificity/accuracy of 83.5 ± 5.5 %/93.7 ± 1.9 %/82.4 ± 2.0 %. The inclusion of Agatston-score-derived and fat-omics features significantly improved classification performance. Survival analyses showed that both actual and predicted obstructive CAD significantly differentiated patients who experienced MACE and revascularization. CONCLUSIONS: We developed a novel machine learning model to predict obstructive CAD from non-contrast CTCS scans. Our findings highlight the potential clinical benefits of CTCS imaging in identifying patients likely to benefit from advanced imaging.