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We aimed to assess the diagnostic and prognostic value of ST-segment deviation in aVR, a lead often ignored in clinical practice, during exercise testing and to compare it to the most widely used criterion of ST-segment depression in V 5 . We enrolled 1,596 patients with suspected myocardial ischemia referred for nuclear perfusion imaging undergoing bicycle stress testing. ST-segment amplitudes in leads aVR and V 5 were automatically measured. The presence of inducible myocardial ischemia was the diagnostic end point and adjudicated based on nuclear perfusion imaging and coronary angiography. Major adverse cardiac events (MACE) during 2 years of follow-up including death, acute myocardial infarction, and coronary revascularization were the prognostic end point. Exercise-induced myocardial ischemia was detected in 470 patients (29%). Median ST amplitudes for leads aVR and V 5 differed significantly among patients with and without ischemia (p <0.01). The diagnostic accuracy of ST changes for myocardial ischemia as quantified by the area under the receiver operating characteristic curve was highest 2 minutes into recovery and similar in aVR and V 5 (0.62, 95% confidence interval CI 0.60 to 0.65 vs 0.60, 95% confidence interval 0.58 to 0.63, p = 0.08 for comparison). In multivariate analysis, ST changes in lead aVR, but not lead V 5 , contributed independent diagnostic information on top of clinical parameters and manual electrocardiographic interpretation. Within 2 years of follow-up, MACE occurred in 33% of patients with ST elevations in aVR and in 16% without (p <0.001). In conclusion, ST elevation in lead aVR during exercise testing indicates inducible myocardial ischemia independently of ST depressions in lead V 5 and clinical factors and also predicts MACE during follow-up., (Copyright © 2017 Elsevier Inc. All rights reserved.)