Objectives.: This study compared the diagnostic accuracy of exercise thallium-201 single-photon emission computed tomography (SPECT) with the exercise electrocardiographic (ECG) response in patients with normal baseline ECG results. Background.: Previous studies comparing exercise thallium imaging with exercise electrocardiography have included patients with abnormal rest ECG results that may have biased the results in favor of thallium imaging. Methods.: Of 321 patients with a pretest likelihood of coronary artery disease of 70 ± 29% (mean ± SD) who underwent exercise stress testing and coronary angiography, 68 had no coronary artery disease; 94 had one-vessel disease; 79 had two-vessel disease; and 80 had three-vessel or left main coronary artery disease. Results.: The diagnostic accuracy of SPECT was higher than that of the ECG response (79% vs. 49%, p < 0.0001). Patients with extensive (left main or three-vessel) coronary artery disease were older and had a lower work load, lower heart rate, greater ST segment depression and more extensive perfusion abnormalities than patients with no disease or one- or two-vessel disease. Multivariate discriminant analysis of exercise and thallium variables identified multivessel thallium abnormalities (F = 35), exercise heart rate (F = 18) and extent of ST segment depression (F = 6) as independent predictors of extensive disease. Of the 80 patients with left main or three-vessel disease, 37 (46%) had ≥2-mm ST segment depression, 44 (55%) had multivessel SPECT abnormalities, and 61 (76%) had either ≥2-mm ST depression or multivessel SPECT abnormalities (p = 0.0005 vs. the ECG response; p = 0.01 vs. SPECT). Conclusions.: In patients with an intermediate to high pretest probability of coronary artery disease and normal baseline ECG results, SPECT is superior to the ECG response in detecting coronary disease. Further, SPECT provides incremental power in identifying patients with extensive (left main or three-vessel) coronary disease. © 1995 American College of Cardiology.