To evaluate the diagnostic accuracy of 64-slice CT coronary angiography (CT-CA) for the detection of significant coronary artery stenosis in patients with zero on the Agatston Calcium Score (CACS). We enrolled 279 consecutive patients (96 male, mean age 48±12 years) with suspected coronary artery disease. Patients were symptomatic (n=208) or asymptomatic (n=71), and underwent conventional coronary angiography (CAG). For CT-CA we administered an IV bolus of 100 ml of iodinated contrast material. CT-CA was compared to CAG using a threshold for significant stenosis of ≤50%. The prevalence of disease demonstrated at CAG was 15% (1.4% in asymptomatic). The population at CAG showed no or non-significant disease in 85% (238/279), single vessel disease in 9% (25/279), and multi-vessel disease in 6% (16/279). Sensitivity, specificity, and positive and negative predictive values of CT-CA vs. CAG on the patient level were 100%, 95%, 76%, and 100% in the overall population and 100%, 100%, 100%, and 100% in asymptomatic patients, respectively. CT-CA proves high diagnostic performance in patients with or without symptoms and with zero CACS. The prevalence of significant disease detected by CT-CA was not negligible in asymptomatic patients. The role of CT-CA in asymptomatic patients remains uncertain.