To assess the capability of a zero coronary artery calcium (CAC) score to help exclude flow-limiting coronary artery disease (CAD) in a homogeneous population with stable anginal complaints and a low-to-intermediate pretest likelihood. The study protocol had institutional ethics committee approval, with written informed consent from all patients. Between 2009 and 2011, a total of 3501 consecutive stable patients without known CAD underwent prospectively simultaneous myocardial perfusion imaging and CAC scoring on a hybrid, 64-section single photon emission computed tomography (SPECT)/computed tomography (CT) scanner. In 868 (25%) of 3501 patients, the CAC score was zero, and these patients constituted the current study population. When feasible, additional coronary CT angiography was performed in those with abnormal SPECT findings. Clinical follow-up was recorded with regard to invasive coronary angiography, coronary revascularization, nonfatal myocardial infarction, or death. Results were analyzed by using descriptive statistics. In 868 patients (mean age, 54 years ± 11 [standard deviation]; 610 [70%] female, 258 [30%] male), SPECT findings were normal in 766 (88%) and abnormal in 102 (12%), with equivocal results in 41 (5%), persistent defect in 35 (4%), and ischemia in 26 (3%). In the group with abnormal SPECT findings, additional coronary CT angiography was performed in 93 patients (91%), showing nonobstructive CAD in eight patients (9%) and normal coronary arteries in 85 patients (91%). In the other nine patients (9%), invasive angiography was used to exclude obstructive CAD. At a median follow-up of 17 months (25th percentile, 11; 75th percentile, 24 months), no coronary events were recorded. A CAC score of zero in stable patients at low or intermediate risk excludes flow-limiting CAD. These findings support the possibility of CAC scoring as a simple and safe tool to select patients for additional testing or discharge, as recommended in the literature.