To determine the natural history of myocardial infarction (MI) in the absence of angiographically significant (no lesion greater than or equal to 50% diameter stenosis) fixed coronary artery disease (CAD), clinical and angiographic data and late outcome were studied in 43 such patients. The mean age was 45 +/- 11 years; 32 patients (74%) were cigarette smokers. Mild fixed CAD, present in 38 patients (88%), was more frequent in the artery supplying the MI zone (p less than 0.01). Filling defects or serial angiographic resolution of obstruction in the artery supplying the MI zone were present in 14 patients (33%). At late follow-up, 14 major cardiac events occurred in 9 patients, including revascularization in 3, recurrent MI in 6 and cardiac death in 5. Of 35 patients undergoing catheterization within 1 year of the index MI, cumulative risk of a major cardiac event was 9 +/- 4, 12 +/- 5 and 20 +/- 7% at 3, 19 and 37 months, respectively. Myocardial infarction in the absence of significant fixed CAD tends to occur in young smokers with mild CAD in the artery serving the MI zone. Superimposed intracoronary thrombus can be frequently implicated. In these patients, subsequent major cardiac events may occur more frequently than previously reported.