Background: Coronary artery calcification (CAC) is widely accepted as a quantitative index of subclinical atherosclerosis in the coronary artery, and is utilized as a valuable tool for the global risk assessment of cardiovascular events in individuals at intermediate risk. However, the association between CAC and ischemic stroke has not been evaluated. Methods: CAC scores were measured in 401 consecutive first-ever acute ischemic stroke patients and in 5,420 healthy subjects who underwent detailed medical health screening. The authors randomly matched case:referent sets (1:2) for gender, age, hypertension, diabetes and hyperlipidemia. Accordingly, 290 stroke cases were matched with 580 referent controls. Results: Moderate-to-extensive CAC (CAC ≧100) was detected in 78 (26.9%) of the ischemic stroke cases and in 120 (20.7%) of the referent controls. Conditional logistic regression analysis, which was conducted to investigate the association between categorized CAC scores and ischemic stroke, and adjusted for other relevant confounders, revealed that moderate-to-extensive CAC was associated with the occurrence of ischemic stroke (OR 1.72, 95% CI 1.05–2.80, compared to the subjects with no CAC). The mean ± SE of the AUC-ROC curve for Framingham risk score (FRS) plus CAC score (0.760 ± 0.018) was significantly greater than that of FRS alone (0.748 ± 0.018; p = 0.005). Conclusions: Our results demonstrate that moderate-to-extensive CAC is associated with an increased occurrence of ischemic stroke. In view of the contribution made by CAC to the risk assessment of cardiovascular diseases, the CAC score may be utilized to evaluate the risk of ischemic stroke.