Objective Transmural myocardial ischemia induces changes in QRS complex and QT interval duration but, theoretically, these changes might not occur in acute pericarditis provided that the injury is not transmural. This study aims to assess whether QRS and QT duration permit distinguishing acute pericarditis and acute transmural myocardial ischemia. Methods Clinical records and 12-lead electrocardiogram (ECG) at ×2 magnification were analyzed in 79 patients with acute pericarditis and in 71 with acute ST-segment elevation myocardial infarction (STEMI). Results ECG leads with maximal ST-segment elevation showed longer QRS complex and shorter QT interval than leads with isoelectric ST segment in patients with STEMI (QRS: 85.9 ± 13.6 ms vs 81.3 ± 10.4 ms, P = .01; QT: 364.4 ± 38.6 vs 370.9 ± 37.0 ms, P = .04), but not in patients with pericarditis (QRS: 81.5 ± 12.5 ms vs 81.0 ± 7.9 ms, P = .69; QT: 347.9 ± 32.4 vs 347.3 ± 35.1 ms, P = .83). QT interval dispersion among the 12-ECG leads was greater in STEMI than in patients with pericarditis (69.8 ± 20.8 ms vs 50.6 ± 20.2 ms, P <.001). The diagnostic yield of classical ECG criteria (PR deviation and J point level in lead aVR and the number of leads with ST-segment elevation, ST-segment depression, and PR-segment depression) increased significantly (P = .012) when the QRS and QT changes were added to the diagnostic algorithm. Conclusions Patients with acute STEMI, but not those with acute pericarditis, show prolongation of QRS complex and shortening of QT interval in ECG leads with ST-segment elevation. These new findings may improve the differential diagnostic yield of the classical ECG criteria.