Multidetector coronary computed tomographic angiography (CCTA) demonstrates high accuracy for the detection and exclusion of coronary artery disease (CAD) and predicts adverse prognosis. To date, opportunity costs relating the clinical and economic outcomes of CCTA compared with other methods of diagnosing CAD, such as myocardial perfusion single-photon emission computed tomography (SPECT), remain unknown. An observational, multicenter, patient-level analysis of patients without known CAD who underwent CCTA or SPECT was performed. Patients who underwent CCTA (n = 1,938) were matched to those who underwent SPECT (n = 7,752) on 8 demographic and clinical characteristics and 2 summary measures of cardiac medications and co-morbidities and were evaluated for 9-month expenditures and clinical outcomes. Adjusted total health care and CAD expenditures were 27% (p <0.001) and 33% (p <0.001) lower, respectively, for patients who underwent CCTA compared with those who underwent SPECT, by an average of $467 (95% confidence interval $99 to $984) for CAD expenditures per patient. Despite lower total health care expenditures for CCTA, no differences were observed for rates of adverse cardiovascular events, including CAD hospitalizations (4.2% vs 4.1%, p = NS), CAD outpatient visits (17.4% vs 13.3%, p = NS), myocardial infarction (0.4% vs 0.6%, p = NS), and new-onset angina (3.0% vs 3.5%, p = NS). Patients without known CAD who underwent CCTA, compared with matched patients who underwent SPECT, incurred lower overall health care and CAD expenditures while experiencing similarly low rates of CAD hospitalization, outpatient visits, myocardial infarction, and angina. In conclusion, these data suggest that CCTA may be a cost-efficient alternative to SPECT for the initial coronary evaluation of patients without known CAD.