We sought to assess the relation between myocardial ischemia during stress echocardiography and major events in patients with implantable cardioverter-defibrillator (ICD). The association of myocardial ischemia with subsequent ICD therapy and mortality is unknown. We studied 90 patients (age 65 +/- 13 years, 27 women) with history of coronary heart disease who received ICD for primary (53 patients) or secondary (37 patients) prevention of sudden cardiac death. Sixty-five (72%) patients had a previous coronary artery bypass surgery. Patients underwent exercise treadmill or dobutamine stress echocardiography. Ischemia was defined as new or worsening wall motion abnormalities. End points were death and appropriate ICD therapy. Mean ejection fraction was 34 +/- 12%. During a mean follow-up of 2.8 +/- 1.5 years, 5 patients died and 19 patients had ICD therapy. Ischemia was detected in 20 of 24 patients with subsequent events and in 24 of 66 patients without (83% vs. 36%, p < 0.001). Events occurred in 17 of the 32 patients (53%) with both ischemia and inducible ventricular tachycardia (VT) on electrophysiologic (EP) studies. None of the 16 patients without ischemia or inducible VT on EP studies had events. In a Cox multivariate analysis model, independent predictors of events were a history of spontaneous sustained VT (hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.3 to 3.8), inducible VT on EP studies (HR 1.7, 95% CI 1.2 to 4.5), and ischemia (HR 2.1, 95% CI 1.2 to 3.5). Ischemia during stress echocardiography is an independent predictor of death and ICD therapy in patients with coronary heart disease at high risk of arrhythmic death. Patients without inducible ischemia or VT on a previous EP study have a very low risk of events. A combination of ischemia and a positive EP study is associated with a very high risk of events.