Guidelines recommend that patients with suggestive symptoms of myocardial ischemia and ST-segment elevation (STE) in ≥2 adjacent electrocardiographic leads should receive immediate reperfusion therapy. Novel strategies aimed to reduce door-to-balloon time, such as prehospital wireless electrocardiographic transmission, may be dependent on the interpretation accuracy of the electrocardiogram (ECG) readers. We assessed the ability of experienced electrocardiographers to differentiate among STE, acute STE myocardial infarction (STEMI), and nonischemic STE (NISTE). A total of 116 consecutive ECGs showing STE were studied. Fifteen experienced cardiologists were asked to decide, based on the ECG and assuming that the patient had compatible symptoms, whether they would send each patient for primary percutaneous coronary intervention (PPCI). If NISTE was chosen, the reader selected 1 or more 12 possible options to explain the choice. Of 116 patients, only 8 had STEMI. The percentage of ECGs for which PPCI was recommended for the patient by the individual readers varied widely (7.8% to 33%). There was no significant difference between the North American and Other Countries readers (p = 0.13). The sensitivity and specificity of the individual readers ranged from 50% to 100% (average 75%) and 73% to 97% (average 85%), respectively. There were broad inconsistencies among the readers in the chosen reasons used to classify NISTE. In conclusion, we found wide variations among experienced electrocardiographers in reading ECGs with STE and differentiating STEMI with need for PPCI from NISTE. There is a need to revise our current electrocardiographic criteria for differentiating STEMI from NISTE.