The significance of inferior ST segment changes during acute anterior myocardial infarction was studied in 60 patients with acute anterior infarction who had angiographic visualization of the entire distribution of the left anterior descending artery after thrombolytic therapy with streptokinase. In 34 patients (Group 1) this artery supplied the anterior wall of the left ventricle up to or including the apex but did not reach the inferior wall; in 16 patients (Group 2) it continued beyond the apex onto the inferior wall of the left ventricle; and in 10 patients with prior inferior infarction (Group 3) it partially supplied the inferior wall of the left ventricle through collateral channels to an occluded right or dominant circumflex coronary artery. Consistent with this anatomy, evidence of inferior wall ischemia was significantly more frequent in Groups 2 and 3 than in Group 1 by thallium-201 scintigraphy (91 versus 7%) and by contrast left ventriculography (91 versus 13%). There was no difference in the magnitude of precordial ST segment elevation among the three groups but the inferior ST segment depression was significantly smaller in Groups 2 and 3 with concomitant inferior wall ischemia than in Group 1 (aVF: −0.5 ± 0.7; −0.5 ± 1.0; −1.8 ± 0.8 mm, respectively; p < 0.001) with 10 of the 26 patients in Groups 2 and 3 having an elevated or isoelectric ST segment in aVF compared with none of the 34 patients in Group 1 (p < 0.001). In patients with inferior ST segment depression, a ratio of ST depression in lead aVF to ST elevation in lead V2 that was less negative than −0.2 was a reliable marker of concomitant inferior wall ischemia. The data suggest that the electrocardiogram can identify patients with anterior infarction who have concomitant inferior wall ischemia due to occlusion of a left anterior descending artery that either also supplies the inferior wall or is the source of collateral flow to a previously occluded posterior descending artery in patients with prior inferior infarction.