Background: The guidelines for evaluation and diagnosis of stable chest pain (SCP) released by American societies in 2021 (2021 GL) and European Society of Cardiology (ESC) in 2019 both recommended the estimation of pretest probability (PTP) by ESC-PTP model. Further risk assessment for the low-risk group according to 2021 GL (ESC-PTP \le15%) is important but still remains unclear. Thus, the present study intended to comprehensively investigate the diagnostic and prognostic value of coronary artery calcium score (CACS) in these low-risk patients. Methods: From January 2017 to June 2019, we initially enrolled 8265 patients who were referred for CACS and coronary computed tomography angiography (CCTA) for the assessment of SCP. PTP of each patient was estimated by ESC-PTP model. Patients with ESC-PTP \le15% were finally included and followed up for major adverse cardiovascular event (MACE) and utilization of invasive procedures until June 2022. The degree of coronary artery disease (CAD) on CCTA was defined as no CAD (0%), nonobstructive CAD (1–49%) and obstructive CAD (\ge50%). Multivariate Cox proportional hazards and Logistic regression models were used to calculate adjusted hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs), respectively. Results: A total of 5183 patients with ESC-PTP \le15% were identified and 1.6% experienced MACE during the 4-year follow-up. The prevalence of no CAD and obstructive CAD decreased and increased significantly (p 0.0001) in patients with higher CACS, respectively, and 62% had nonobstructive CAD among those with CACS >0, resulting in dramatically increasing ORs for any stenosis \ge50% and >0% across CACS strata. Higher CACS was also associated with an elevated risk of MACE (adjusted HR of 3.59, 13.47 and 6.58 when comparing CACS = 0–100, CACS >100 and CACS >0 to CACS = 0, respectively) and intensive utilization of invasive procedures. Conclusions: In patients for whom subsequent testing should be deferred according to 2021 GL, high CACS conveyed a significant probability of substantial stenoses and clinical endpoints, respectively. These findings support the potential role of CACS as a further risk assessment tool to improve clinical management in these low-risk patients.