A 12-lead electrocardiogram (ECG) reconstructed from a reduced subset of leads is desired in continued arrhythmia and ST monitoring for less tangled wires and increased patient comfort. However, the impact of reconstructed 12-lead lead ECG on clinical ECG diagnosis has not been studied thoroughly. This study compares the differences between recorded and reconstructed 12-lead diagnostic ECG interpretation with 2 commonly used configurations: reconstruct precordial leads V(2), V(3), V(5), and V(6) from V(1),V(4), or reconstruct V(1), V(3), V(4), and V(6) from V(2),V(5). Limb leads are recorded in both configurations. A total of 1785 ECGs were randomly selected from a large database of 50,000 ECGs consecutively collected from 2 teaching hospitals. ECGs with extreme artifact and paced rhythm were excluded. Manual ECG annotations by 2 cardiologists were categorized and used in testing. The Philips resting 12-lead ECG algorithm was used to generate computer measurements and interpretations for comparison. Results were compared for both arrhythmia and morphology categories with high prevalence interpretations including atrial fibrillation, anterior myocardial infarct, right bundle-branch block, left bundle-branch block, left atrial enlargement, and left ventricular hypertrophy. Sensitivity and specificity were calculated for each reconstruction configuration in these arrhythmia and morphology categories. Compared to recorded 12-leads, the V(2),V(5) lead configuration shows weakness in interpretations where V(1) is important such as atrial arrhythmia, atrial enlargement, and bundle-branch blocks. The V(1),V(4) lead configuration shows a decreased sensitivity in detection of anterior myocardial infarct, left bundle-branch block (LBBB), and left ventricular hypertrophy (LVH). In conclusion, reconstructed precordial leads are not equivalent to recorded leads for clinical ECG diagnoses especially in ECGs presenting rhythm and morphology abnormalities. In addition, significant accuracy reduction in ECG interpretation is not strongly correlated with waveform differences between reconstructed and recorded 12-lead ECGs.