This study was performed to compare a derived 12-lead electrocardiogram (ECG) using a simple 5-electrode lead configuration (EASI 12-lead) with the standard ECG for multiple cardiac diagnoses. Accurate diagnosis of arrhythmias and ischemia often require analysis of multiple (ideally, 12) ECG leads; however, continuous 12-lead monitoring is impractical in hospital settings. EASI and standard ECGs were compared in 540 patients, 426 of whom also had continuous 12-lead ST segment monitoring with both lead methods. Independent standards relative to a correct diagnosis were used whenever possible, for example, echocardiographic data for chamber enlargement-hypertrophy, and troponin levels for acute infarction. Percent agreement between the 2 methods were: cardiac rhythm, 100%; chamber enlargement-hypertrophy, 84%-99%; right and left bundle branch block, 95% and 97%, respectively; left anterior and posterior fascicular block, 97% and 99%, respectively; prior anterior and inferior infarction, 95% and 92%, respectively. There was very little variation between the 2 lead methods in cardiac interval measurements; however, there was more variation in P, QRS, and T-wave axes. Of the 426 patients with ST monitoring, 138 patients had a total of 238 ST events (26, acute infarction; 62, angioplasty-induced ischemia; 150, spontaneous transient ischemia). There was 100% agreement between the 2 methods for acute infarction, 95% agreement for angioplasty-induced ischemia, and 89% agreement for transient ischemia. EASI and standard 12-lead ECGs are comparable for multiple cardiac diagnoses; however, serial ECG changes (eg, T-wave changes) should be assessed using one consistent 12-lead method.