Exercise thallium-201 imaging using single-photon emission computed tomography (SPECT) was evaluated in 154 patients with angiographically documented coronary artery disease (CAD) and in 25 normal subjects. Of the 154 patients with CAD, 134 (87%) had abnormal thallium images. By contrast, only 77 (50%) patients had ischemic ST-segment depression (p < 0.001). Among 25 normal subjects, 20 had normal exercise SPECT images. The specificity of exercise SPECT imaging (80% or 20/25) in excluding patients with CAD was not significantly higher than that of exercise electrocardiography (76% or 19/25). For the detection of individual vessel involvement by analysis of territories of perfusion abnormalities, the sensitivity and specificity of exercise SPECT were 72% and 96% for the left anterior descending, 78% and 85% for the right coronary, and 47% and 98% for the left circumflex artery. Ninety (group 1) of the 154 patients with CAD achieved adequate exercise end points (ischemic ST-segment depression or > 85% of maximal predicted heart rate) and 64 (group 2) did not. Exercise SPECT showed significantly more perfusion abnormalities in group 1 than in group 2 (96% vs 75%, p < 0.001). We conclude that: (1) exercise SPECT thallium imaging is more sensitive than exercise electrocardiography for detecting patients with CAD; (2) the sensitivity of the test is affected by the level of exercise; and (3) it is valuable in the identification of individual vessel involvement.