Current guidelines state that patients with compatible symptoms and ST-segment elevation (STE) in ≥2 contiguous electrocardiographic leads should undergo immediate reperfusion therapy. Aggressive attempts at decreasing door-to-balloon times have led to more frequent activation of primary percutaneous coronary intervention (pPCI) protocols. However, it remains crucial to correctly differentiate STE myocardial infarction (STEMI) from nonischemic STE (NISTE). We assessed the ability of experienced interventional cardiologists in determining whether STE represents acute STEMI or NISTE. Seven readers studied electrocardiograms of consecutive patients showing STE. Patients with left bundle branch block or ventricular rhythms were excluded. Readers decided if, based on electrocardiographic results, they would have activated the pPCI protocol. If NISTE was chosen, readers selected from 12 possible explanations as to why STE was present. Of 84 patients, 40 (48%) had adjudicated STEMI. The percentage for which readers recommended pPCI varied (33% to 75%). Readers' sensitivity and specificity ranged from 55% to 83% (average 71%) and 32% to 86% (average 63%), respectively. Positive and negative predictive values ranged from 52% to 79% (average 66%) and 67% to 79% (average 71%), respectively. Broad inconsistencies existed among readers as to the chosen reasons for NISTE classification. In conclusion, we found wide variations in experienced interventional cardiologists in differentiating STEMI with a need for pPCI from NISTE.