Background: In ST-elevation myocardial infarction (STEMI), the use of ECG in the acute phase contains useful information, including the lesion location, and it contributes to the appropriate treatment. We sought to evaluate the culprit artery in patients with STEMI through ECG variations and its relation with the culprit lesion identified on angiography. Methods: Patients referring to Rajaie Cardiovascular, Medical, and Research Center between September 2011 and September 2012, due to acute MI accompanied by STEMI were chosen. Based on the ECG, the culprit artery was determined and the amount of ST- elevation in every lead was recorded. On angiography, the exact location of the closure in the main coronary vessels and/or side branches was identified. The findings were adjusted to the ECG, and its ability in the prediction of the culprit lesion was assessed. Results: We studied 100 patients, comprising 17 female and 83 male patients, at an average age of 57.64±11.31 years. The introduced model of ECG was useful for the prediction of the lesion in the proximal right coronary artery (RCA), mid left anterior descending artery (LAD) before D1 after S1, and proximal LAD and the least predictive ability was for the distal LAD and the distal RCA. The relationship between the proximal LAD and ST-elevation >2.5 mm in V1 was significant, and the relationships between the mid LAD before D1 after S1 and QAVL, Q in V4-V6, ST-depression >1 mm in III and no ST-depression in II and AVF were significant as well. Conclusions: Our results demonstrated that in patients with STEMI, ECG was able to reliably predict the location of the culprit lesion in most vessels such as the proximal RCA and the mid LAD before D1 after S1. (Iranian Heart Journal 2016; 17(1): 6-13)