This study was performed to determine whether inferior ST segment depression during early stages of acute transmural anterior myocardial infarction identifies patients with multivessel coronary artery disease and additional inferior ischemia. Coronary and left ventricular angiography were performed within 3.4 months in 33 patients with acute transmural anterior infarction. Initial electrocardiograms, 2 to 5 hours after onset of chest pain, revealed significant ST segment depression (greater than or equal to 0.1 mV) in at least two of leads II, III and a VF in 15 patients (45%) (group B); in 18 patients (group A) this finding was absent. Compared with group A, patients in group B had greater anterior ST elevation (1.2 versus 0.7 mV, p less than 0.025); higher serum peak creatine kinase (2,475 versus 1,147 IU/liter, p less than 0.005); higher Killip scores (2.1 versus 1.3, p less than 0.001); more in-hospital complications (60 versus 17%, p less than 0.05); lower mean left ventricular ejection fraction (34 versus 55%, p less than 0.001); more frequent regional left ventricular dysfunction in anterolateral (91 versus 44%, p less than 0.05), posterolateral (36 versus 0%, p less than 0.05) and inferior (100 versus 6%, p less than 0.005) regions; greater wall motion abnormality scores (10.0 versus 5.5, p less than 0.005); higher frequency of concomitant left circumflex or right coronary artery disease, or both (80 versus 28%, p less than 0.01); more frequent postinfarction angina (100 versus 39%, p less than 0.001) and lower New York Heart Association functional classification scores (1.7 versus 2.4, p less than 0.05) at 6 month follow-up. The time course of inferior ST depression differed from that of anterior ST elevation. Thus, inferior ST depression was maximal in the first 48 hours and decreased (p less than 0.05) thereafter. In contrast, ST elevation in leads V1 to V6 and I appeared to decrease (p = NS) between days 4 and 7. However, inferior ST depression "mirrored" ST elevation in lead aVL, which also decreased (p less than 0.05) after 48 hours. Thus, inferior ST depression during anterior infarction is associated with more extensive infarction, greater morbidity and higher frequency of multivessel coronary disease. Such inferior ST depression might reflect not only "reciprocal change," but also ischemia in adjacent lateral and remote inferior regions.