Aim To assess the prognostic significance of ST-segment elevation in lead aVR for patients with first non ST-Segment elevation acute myocardial infarction. Methods Initial ECG in 426 patients with a first acute myocardial infarction without ST-segment elevation in leads other than aVR or V1 were analyzed. Results The rates of in-hospital death in patients without (n=281) and with 0.05 to 0.1 mV (n=68) or ≥0.1 mV (n=77) of ST-segment elevation in lead aVR were 1.8%, 7.4% and 15.6%, respectively (P<0.001). After adjustment for the baseline clinical predictors and for ST-segment depression on admission, the odds ratios of death in the last 2 groups were 4.2 (95% CI was 1.4 to 13.5; P<0.001) and 6.1 (95% CI was 2.4 to 17.3) (P<0.001), respectively. The rates of recurrent ischemic events and heart failure during in-hospital increased in a stepwise fashion among the groups, whereas creatine kinase (CK) and MB isoenzyme of creatine kinase (CK-MB) levels were similar. The prevalence of left main or 3-vessel coronary artery disease in the 3 groups was 16.9%, 37.1% and 56.2%, respectively (P<0.001). Conclusions Lead aVR has short-term prognostic significance in patients with a first non ST-segment elevation acute myocardial infarction. Because the poorer outcome predicted by ST-segment elevation in lead aVR seems to be related to a more severe coronary artery disease, an early invasive approach might be especially beneficial in patients presenting with this finding.