During inferior acute myocardial infarction, ST-segment elevation (ST↑) often occurs in leads V₅ to V₆, but its clinical implications remain unclear. We examined the admission electrocardiograms from 357 patients with a first inferior acute myocardial infarction who had Thrombolysis In Myocardial Infarction 3 flow of the right coronary artery or left circumflex artery within 6 hours after symptom onset. The patients were divided according to the presence (n = 76) or absence (n = 281) of ST↑ >2 mm in leads V₅ and V₆. Patients with ST↑ in leads V₅ and V₆ were subdivided into 2 groups according to the degree of ST↑ in leads III and V₆: ST↑ in lead III greater than in V₆ (n = 53) and ST↑ in lead III equal to or less than in V₆ (n = 23). The perfusion territory of the culprit artery was assessed using the angiographic distribution score, and a mega-artery was defined as a score of ≥0.7. ST↑ in leads V₅ and V₆ with ST↑ in lead III greater than in V₆ and ST↑ in leads V₅ and V₆ with ST↑ in lead III equal to or less than in V₆ were associated with mega-artery occlusion and impaired myocardial reperfusion, as defined by myocardial blush grade 0 to 1. Right coronary artery occlusion was most common (96%) in the former, and left circumflex artery occlusion was most common (96%) in the latter, especially proximal left circumflex occlusion (74%). Multivariate analysis showed that ST↑ in leads V₅ and V₆ with ST↑ in lead III greater than that in V₆ (odds ratio 4.81, p <0.001) and ST↑ in leads V₅ and V₆ with ST↑ in lead III equal or less than that in V₆ (odds ratio 5.96, p <0.001) were independent predictors of impaired myocardial reperfusion. In conclusion, ST↑ in leads V₅ and V₆ suggests a greater risk area and impaired myocardial reperfusion in patients with inferior acute myocardial infarction. Furthermore, comparing the degree of ST↑ in lead V₆ with that in lead III is useful for predicting the culprit artery.