Despite a growing awareness of the correlation of coronary artery stenoses morphology with clinical syndromes, no comprehensive, prospective analysis of the implications of stenosis morphology on risk of myocardial infarction has been reported. Angiograms from 118 patients, representative of the 4.9% of medically treated Coronary Artery Surgery Study (CASS) patients who during subsequent 3 year follow-up study had an anterior myocardial infarction, were matched on the basis of arteriographic anatomy and disease with 141 patients who did not have an anterior infarction. Angiograms from these 259 patients with 557 left anterior descending artery stenoses were reviewed without knowledge of clinical outcome. Conditional regression analyses were performed to determine the importance of stenosis morphology, relative to computer-determined stenosis severity and other clinical variables, in the prediction of risk of infarction. Univariate analysis revealed luminal roughness (odds ratio 4.5; p = 0.001) and lesion length (odds ratio 1.7 per unit length; p = 0.007) to be highly correlated with future risk of infarction. Multivariate analysis revealed left anterior descending artery percent stenosis greater than or equal to 50%, lesion roughness, left circumflex artery stenosis and smoking, in that order, to be predictive of anterior myocardial infarction, whereas 22 other morphologic variables were not independently predictive of outcome. The importance of stenosis roughness may relate to its propensity for thrombogenesis and should be considered in clinical decision making.