© 2019 Previously reported electrocardiographic (ECG) criteria to distinguish left circumflex (LCCA) and right coronary artery (RCA) occlusion in patients with acute inferior ST-segment elevation myocardial infarction (STEMI) afford a modest diagnostic accuracy. We aimed to develop a new algorithm overcoming limitations of previous studies. Clinical, ECG, and coronary angiographic data were analyzed in 230 nonselected patients with acute inferior STEMI who underwent primary percutaneous coronary intervention. A decision-tree analysis was used to develop a new ECG algorithm. The diagnostic accuracy of reported ECG criteria was reviewed. LCCA occlusion occurred in 111 cases and RCA in 119. We developed a 3-step algorithm that identified LCCA and RCA occlusion with a sensitivity of 77%, specificity of 86%, accuracy of 82%, and Youden index of 0.63. The area under the ROC curve was 0.85 and resulted 0.82 after a 10-fold cross validation. The key leads for LCCA occlusion were V3 (ST depression in V3/ST elevation in III >1.2) and V6 (ST elevation ≥0.1 mV or greater than III). The key leads for RCA occlusion were I and aVL (ST depression ≥ 0.1 mV). Fifteen of 21 reviewed studies had less than 20 cases of LCCA occlusion, only 48% performed primary percutaneous coronary intervention, and previous infarction or multivessel disease were often excluded. The diagnostic accuracy of reported ECG criteria decreased when applied to our study population. In conclusion, we report a simple and highly discriminative 3-step ECG algorithm to differentiate LCCA and RCA occlusion in an “all comers” population of patients with acute inferior STEMI. The diagnostic key ECG leads were V3 and V6 for LCCA and I and aVL for RCA occlusion.