This blinded, single center study prospectively compares exercise electron beam computed tomography (EBCT) with stress technetium-99m (Tc-99m) sestamibi single-photon emission computed tomography (SPECT) in 33 patients undergoing coronary angiography for evaluation of chest pain. Patients undergoing routine cardiac catheterization for the diagnosis of chest pain were imaged at rest using EBCT. Patients exercised on a semi-supine ergometer, and exercise EBCT was immediately followed by injection of Tc-99m sestamibi for assessment of myocardial ischemia. At peak exercise, Tc-99m SPECT, followed immediately by nonionic contrast material, was injected intravenously to directly compare these 2 imaging techniques. Patients were reimaged with Tc-99m SPECT at rest 24 to 48 hours after stress. Exercise EBCT, which was analyzed using a global ejection fraction measure, had a sensitivity of 81% and a specificity of 76%, compared with angiography. Using the development of a new regional wall motion abnormality as evidence of obstructive coronary artery disease (CAD), EBCT yielded a specificity of 100% and a sensitivity of 88%. Reversible perfusion defects identified by SPECT, as evidence of obstructive CAD, revealed a sensitivity of 75% and a specificity of 71%. The specificity of regional wall motion analysis by EBCT was significantly better than SPECT (p <0.01) in this population. This study demonstrates regional wall motion assessed by EBCT to be as sensitive and more specific than SPECT myocardial perfusion imaging in identifying obstructive CAD as defined by angiography.