Despite its limited sensitivity and specificity in patients with low to intermediate probability of coronary artery disease (CAD), exercise treadmill testing (ETT) is frequently used as the initial test for investigation of chest pain. Although myocardial perfusion imaging is a significantly more accurate test, its added cost to ETT is considerable. The cost of a non-contrast electron beam computed tomography (EBCT) scan is comparable to that of ETT and the calcium score (CS) correlates closely with the volume of atherosclerotic plaque. Therefore, we tested the hypothesis that EBCT might be an effective and cost-beneficial technique for the identification of angiographically obstructive CAD (> or = 50% stenosis) in patients with low to intermediate pretest probability of disease. We calculated the theoretic cost of attaining a diagnosis of CAD based on a Bayesian model that utilizes published sensitivity and specificity levels for ETT, EBCT, and stress myocardial perfusion imaging. We then submitted a cohort of 207 patients with low to intermediate probability of disease both to EBCT and ETT in random order, and estimated the cost of achieving a correct diagnosis by either route based on the number of expected further tests. An EBCT calcium score of 150 was chosen as a cut-point with a sensitivity of 74% and a specificity of 89% for the presence of obstructive CAD. The theoretic Bayesian model predicted substantial cost savings when EBCT was used as the initial test instead of ETT, with decreasing benefit as the prevalence of disease increased (44% saving at 0% prevalence; 15% saving at 100% prevalence). In the patient cohort, the diagnostic pathway starting with EBCT provided a 45% to 65% cost saving over the ETT pathway. We conclude that in patients with low to intermediate pretest probability of disease, a pathway based on EBCT as the initial test to investigate presence of obstructive CAD provides a substantial cost benefit over a pathway based on ETT. Such cost advantages decrease as the prevalence of disease increases.