Increased lung thallium uptake during exercise is an important marker of patients who are at high risk and have CAD; however, most previous studies were done with planar imaging, and therefore it is unclear whether this conclusion is also true with SPECT imaging. This study examined the lung thallium uptake during exercise SPECT imaging in 1031 patients who also underwent coronary angiography. The lung thallium uptake was increased in 309 patients (group 1) and normal in 722 patients (group 2). Compared with patients in group 2, those in group 1 had more ST segment depression (44% vs 28%, p = 0.01), previous Q-wave myocardial infarction (28% vs 17%, p = 0.0001), larger perfusion defects (24% +/- 11% vs 10% +/- 11%, p = 0.0001), and multivessel CAD by angiography (75% vs 47%, p = 0.0001). Multivariate discriminant analysis identified left ventricular dilation, reversible defects, the size of perfusion abnormality, and the extent of CAD as independent predictors of increased lung thallium uptake. Increased lung thallium uptake was more common in men than women regardless of the extent of CAD: 26% versus 11% in patients with one-vessel, 38% versus 18% in patients with two-vessel, and 51% versus 31% in patients with three-vessel disease (p < 0.001 each). Thus increased lung thallium uptake by SPECT identifies patients with more severe anatomic and functional evidence of CAD. The sex-related difference suggests the need for a sex-specific normal file for quantitative analysis.