In a few patients, 12-lead electrocardiograms (ECGs) derived from reduced-lead-set configurations do not match the standard ECG. Constructing an ECG from a reduced number of standard leads should minimize this problem because some of the resultant 12 leads would always include "true" standard leads. The purpose of this study was to compare the ability of a new reduced-lead-set 12-lead ECG ("interpolated" ECG) with the standard ECG to diagnose cardiac arrhythmias and acute myocardial ischemia. The interpolated ECG uses six standard electrode sites (limb leads plus V(1) and V(5)), from which the remaining four precordial leads (V(2), V(3), V(4), and V(6)) are constructed. Standard and interpolated ECGs were compared using data from 2 prospective clinical trials involving 649 patients evaluated for 1) chest pain in the emergency department (ischemia group, n = 509) or 2) tachycardias in the cardiac electrophysiology laboratory (arrhythmia group, n = 140). Diagnoses were identical between standard and interpolated ECGs for bundle branch and fascicular blocks, left atrial enlargement, right ventricular hypertrophy, prior inferior myocardial infarction (MI), and the distinction of ventricular tachycardia from supraventricular tachycardia with aberrant conduction. There was 99% agreement for prior anterior MI (kappa, .935, P =.000). The percent agreement for acute myocardial ischemia on the initial ECG recorded in chest-pain patients in the emergency department was 99.2% (kappa, .978, P =.000). Of the 120 patients who had ST events with continuous standard 12-lead ECG monitoring, 116 (97%) also had criteria for transient ischemia with the interpolated ECG (ie, DeltaST >or= 100 microV in >or=1 lead(s) lasting >or=1 minute(s). The interpolated 12-lead ECG is comparable to the standard ECG for diagnosing multiple cardiac abnormalities, including wide-QRS-complex tachycardias and acute myocardial ischemia. The advantages of this ECG method are that the standard electrode sites are familiar to clinicians and that eight of the 12 leads are "true" standard leads. Hence, QRS-axis and morphology criteria for diagnosing wide-QRS-complex tachycardia and bundle branch and fascicular blocks are preserved.