This study sought to determine the association of exercise-induced ventricular ectopic activity with thallium perfusion defects and severity of angiographic coronary artery disease (CAD). Two cohorts consisting of adults without heart failure or known severe ventricular ectopic activity at rest were studied. The first cohort consisted of adults (n = 2,743) who underwent maximum exercise thallium stress testing. The second cohort consisted of adults (n = 423) who underwent coronary angiography within 90 days of treadmill testing. Significant exercise-induced ventricular ectopic activity was defined as frequent ventricular premature complexes or nonsustained ventricular tachycardia. Severe CAD was defined as left main CAD (> or = 50% stenosis), 3-vessel CAD (> or = 70% stenosis), or 2-vessel CAD with > or = 70% stenosis of the proximal left anterior descending artery. In the thallium cohort, exercise-induced ventricular ectopic activity was associated with a greater frequency of thallium defects (35.2% vs 18.7%, odds ratio [OR] 2.35, 95% confidence intervals [CI] 1.62 to 3.42, p <0.001); after adjusting for possible confounders, this association persisted (for any defect adjusted OR 1.66, 95% CI 1.09 to 2.53, p = 0.02; for septal defect adjusted OR 2.77, 95% CI 1.51 to 5.07, p <0.001). There was no association between exercise-induced ventricular ectopic activity and mortality during 2 years of follow-up. In the angiographic cohort, there was no association of exercise-induced ventricular ectopy with severe CAD (19% vs 20%, OR 0.93, 95% CI 0.41 to 2.09, p = NS). Exercise-induced ventricular ectopic activity was associated with a greater likelihood of thallium perfusion defects, but was not associated with angiographic severity of coronary disease or with short-term mortality.