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Background: Coronary artery calcium (CAC) scanning can be performed using non-contrast computed tomography to predict cardiovascular events, but has less value for risk stratification in symptomatic patients., Objective: To identify and validate predictors of significant coronary obstruction (SCO) in symptomatic patients without coronary artery calcification., Methods: A total of 4,258 participants were screened from the CORE64 and CORE320 studies that enrolled patients referred for invasive angiography, and from the Quanta Registry that included patients referred for coronary computed tomography angiography (CTA). Logistic regression models evaluated associations between cardiovascular risk factors, CAC, and SCO. An algorithm to assess the risk of SCO was proposed for patients without CAC. Significance level of 5% was used in the analyses., Results: Of the 509 participants of the CORE study, 117 (23%) had zero coronary calcium score; 13 (11%) patients without CAC had SCO. Zero calcium score was related to younger age, female gender, lower body mass index, no diabetes, and no dyslipidemia. Being a current smoker increased ~3.5 fold the probability of SCO and other CV risk factors were not significantly associated. Considering the clinical findings, an algorithm to further stratify zero calcium score patients was proposed and had a limited performance in the validation cohort (AUC 58; 95%CI 43, 72)., Conclusion: A lower cardiovascular risk profile is associated with zero calcium score in a setting of high-risk patients. Smoking is the strongest predictor of SCO in patients without CAC.