In spite of the apparent rising prevalence of non-Q wave myocardial infarction (MI), and the widespread applicability of cardiac enzymes in the diagnosis of myocardial necrosis, all prior published studies have required obligatory ST segment shifts and/or T wave inversions in the diagnosis of non-Q wave MI. Accordingly, the frequency of clinically and enzymatically defined non-Q wave MI without indicative electrocardiogram (ECG) changes has never been assessed, nor has a systematic analysis of serial ECGs and cardiac enzymes been undertaken in a large prospective non-Q wave MI population. We utilized the extensive data base created from the Diltiazem Reinfarction Study of MB-creatine kinase (CK)- confirmed non-Q wave MI, which was a multicenter study of the effect of diltiazem therapy on early reinfarction. Five hundred and seventy-six patients underwent serial ECG analyses on admission, study day 2, study day 3 and at predischarge (10 ± 2 days after trial entry). A total of 2,304 ECGs were analyzed by 5 blinded investigators, and tracings were examined for the presence or absence of definable ST-T wave changes in 2 or more leads within 3 ECG lead groups: anterior = V(1) - V(4); inferior = II, III, aVF; lateral = I, aVL, V(5) - V(6); combination location = 2 or more lead groups; nonlocalizable = no diagnostic ST or T wave abnormalities. CK and MB-CK values were measured at 12-hour intervals throughout the 14-day study period. At study entry, 32 patients (5.5 %) were found, in retrospect, to have had acute Q wave MI at entry, 439 of the remaining 544 patients (81 %) had localizable ECG changes and 105 (19%) did not. Combination location (≥2 lead groups) non-Q wave MI was the most prevalent (48%), followed by lateral location (18%), anterior location (14%) and inferior location (8%). ST segment elevation was noted in 187/544 patients (34%) on the admission ECG, but in only 37 patients (20%) did Q waves develop subsequently. Of note, mean peak CK values were not significantly different among subgroups, and the highest mean CK values were observed in patients with nonlocalizable non-Q wave MI (668 ± 877 vs. 616 ± 26 IU for the remaining localizable subgroups; p = NS). We noted further that 76 of 544 patients (14%) progressed to Q wave MI during the 14-day observation period, and 67 patients (12%) ‘normalized’ their ECGs prior to discharge. Thus, the early ECG findings of non-Q wave MI are most frequently global, less commonly isolated to a single ECG lead group, are attended by a high prevalence of initial ST segment elevation, and are nonlocalizable in almost 20% of patients.