The accuracy of the admission electrocardiogram (ECG) in predicting the site of acute coronary artery occlusion in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease is not well known. This study aimed to assess whether the presence of multivessel coronary artery disease (CAD) modifies the artery-related ST-segment changes in patients with acute coronary artery occlusion. We reviewed the admission ECG, clinical records, and coronary angiography of 289 patients with STEMI caused by acute occlusion of left anterior descending (LAD; n = 140), right (n = 118), or left circumflex (LCx; n = 31) coronary arteries. All patients underwent primary percutaneous coronary reperfusion during the first 12 hours. The magnitude and distribution of artery-related ST-segment patterns were comparable in patients with single (n = 149) and multivessel (n = 140) CAD. Occlusion of proximal (n = 55) or mid-distal (n = 85) LAD artery induced ST-segment elevation in leads V₁ to V₅, but only the proximal occlusion induced reciprocal ST-segment depression in leads II, III, and aVF (p <0.001). Proximal and mid-distal occlusion of right (n = 45 and 73, respectively) or LCx (n = 15 and 16) coronary artery always induced ST-segment elevation in leads II, III, and aVF and reciprocal ST-segment depression in leads V₂ and V₃. ST-segment elevation in lead V₆ >0.1 mV predicted LCx artery occlusion. In conclusion, patients with STEMI with single or multivessel CAD have concordant artery-related ST-segment patterns on the admission ECG; in both groups, reciprocal ST-segment depression in LAD artery occlusion predicts a large infarct. Subendocardial ischemia at a distance is not a requisite for the genesis of reciprocal ST-segment changes.