This study examined the results of exercise-rest same-day SPECT protocol in 193 patients, of whom 132 had coronary artery disease (CAD) by angiography (≤50% diameter stenosis), and 61 had a low pretest probability of CAD. Methods: The rest study was combined with first-pass radionuclide angiography using the multicrystal gamma camera in 72 patients. Results: The sensitivity of SPECT was 76% (25/33 patients) in patients with one-vessel, 84% in patients with two-vessel (38/45) and 98% in patients with three-vessel CAD (53/54) (P = 0.01 versus one- or two-vessel CAD). The sensitivity of SPECT in patients with CAD was higher than ST depression (88% versus 28%, P = 0.001). The exercise was submaximal in 53 patients (40%). The perfusion defects were reversible (complete or partial) in 80 patients and fixed in 36 patients. The left ventricular ejection fraction was 50 ± 12% in patients with reversible defects (n = 44) and 39 ± 9% in patients with fixed defects (n:19) (P = 0.0004). The normalcy rate in subjects with a low pretest probability of CAD was 95% (53 of 61 subjects). Conclusion: The exercise-rest same-day sestamibi protocol provides high diagnostic accuracy for CAD detection. The protocol may eliminate the need for rest studies in patients with normal exercise images, help improve laboratory throughput and lower costs.