Patients with diabetes mellitus experience a more adverse outcome after acute myocardial infarction compared with nondiabetic patients, although the mechanisms responsible for these findings are not clear. From the Multicenter Investigation of the Limitation of Infarct Size (MILIS) study, the course of acute infarction in 85 diabetic patients was compared with that in 415 nondiabetic patients, all of whom had serial assessments of left ventricular function. The diabetic patients experienced a more complicated in-hospital and postdischarge course than did the nondiabetic patients, including a higher incidence of postinfarction angina, infarct extension, heart failure and death, despite the development of a smaller infarct size and similar levels of left ventricular ejection fraction. Although diabetic patients had a worse profile of cardiovascular risk factors at the time of the index infarction, the increased incidence of adverse outcomes among them persisted despite adjustment for these baseline imbalances. Diabetic women had a poor baseline risk profile compared with the other groups categorized by gender and diabetic status, and experienced an almost twofold increase in cardiac mortality despite development of the smallest infarct size during the index event. The duration of diabetes and the use of insulin at the time of the index infarction were associated with a better in-hospital mortality rate, but the duration of diabetes did not exert a major influence on the outcome of the diabetic patients. The factors responsible for the increased incidence of adverse outcomes among diabetic patients may be related to an acceleration of the atherosclerotic process, diastolic left ventricular dysfunction associated with diabetic cardiomyopathy or other unidentified unfavorable processes.