We sought to determine the sensitivity of a change in myoglobin for acute myocardial infarction (AMI) in patients who had normal levels of troponin I at presentation. Myoglobin increases as soon as 1 to 2 hours after symptom onset in AMI. The change in myoglobin may help identify AMI in patients with normal cardiac levels of troponin I on admission. A total of 817 consecutive patients who were examined in the emergency department for possible AMI were studied. In patients whose electrocardiograms were nondiagnostic, we measured levels of myoglobin and cardiac troponin I at presentation, at 90 minutes, and at 3 and 9 hours. Patients whose initial levels of myoglobin (<200 ng/ml) and cardiac troponin I (<0.4 ng/ml) were normal underwent receiver-operating characteristic curve analysis to determine the best cutpoint for a myoglobin increase from 0 to 90 minutes. Overall, 75 patients (9%) were diagnosed with AMI, including 27 patients with normal cardiac levels of troponin I at presentation. An increase of 20 ng/ml of myoglobin from 0 to 90 minutes provided maximal diagnostic utility in patients who did not have increased levels of myoglobin or cardiac troponin I at presentation. In the absence of an increased level of cardiac troponin I or myoglobin at presentation in the emergency department, a change >or=20 ng/ml of myoglobin at 90 minutes produced 83.3% sensitivity, 88.6% specificity, and 99.5% negative predictive value for AMI. The combined sensitivity of levels of cardiac troponin I and myoglobin and a change >or=20 ng/ml of myoglobin over 90 minutes was 97.3%. In emergency department patients with normal cardiac levels of troponin I at presentation, a change in myoglobin provides a highly accurate diagnosis of AMI within 90 minutes.