Sixty-four-detector-row coronary computed tomographic angiography (CCTA) has been proposed for the evaluation of low- to intermediate-risk patients with suspected coronary artery disease (CAD). Historically, exercise treadmill testing (ETT) measures of ST-segment depression (STD) and the Duke treadmill score (DTS) have been used to evaluate myocardial ischemia and functional capacity. The relation of plaque characteristics on CCTA to STD and DTS is unknown. In this study, 156 low- to intermediate-risk patients without known CAD who underwent ETT and CCTA were evaluated. By ETT, 22% (n = 35) had STD and 27% (n = 42) had abnormal DTS. On CCTA, 21% (n = 33) had obstructive CAD (>or=70% stenosis) and 49% (n = 77) had nonobstructive CAD (<70% stenosis). Forty-six percent of patients (n = 16) with and 15% (n = 15) without STD had obstructive CAD. After multivariate adjustment, only age and obstructive CAD on CCTA predicted STD (odds ratio [OR] 1.59, 95% confidence interval [CI] 1.08 to 2.34 per decade, and OR 3.38, 95% CI 1.32 to 8.64, respectively) and abnormal DTS (OR 1.61, 95% CI 1.14 to 2.28, and OR 4.67, 95% CI 1.97 to 11.03, respectively). After adjustment for age, more coronary segments with mixed plaque, in contrast to calcified or noncalcified plaque, predicted STD (OR 1.48, 95% CI 1.18 to 1.85) and abnormal DTS (OR 1.30, 95% CI 1.05 to 1.61). In conclusion, measures of plaque on CCTA identify patients more likely to have STD and higher risk DTS, while providing incremental diagnostic yield for the detection of obstructive CAD beyond ETT.