Analysis of lesion morphology is becoming increasingly important in the study of coronary artery disease. Lesion irregularity has been shown to be one of the most important predictive features for development of myocardial infarction. Most studies to date have used only qualitative assessments of morphology and are thus subject to variability and lack of standardization inherent in subjective visual inspection. We describe a new approach that allows quantitation of lesion morphology. Fifty-nine patients with unstable angina and 17 patients with stable angina were compared. Five morphometric parameters were tested (peaks per centimeter, summed maximum error per centimeter, integrated error per centimeter, number of major features per centimeter, and scaled edge length ratio), four of which were significantly different between the two groups and indicated greater lesion complexity in unstable compared with stable angina patients. No correlation was found between the parameters tested and the degree of luminal narrowing, showing the method's independence from traditional assessments of lesion severity. Excellent intraobserver and interobserver reproducibility was found for all of the parameters. This technique provides a more rigorous approach for analysis of lesion morphology than has previously been available, may provide a method for premorbid detection of high-risk lesions amenable to interventional therapy, and is especially well suited to detect subtle changes in lesion morphology after therapeutic interventions because the parameters are derived on a continuous scale and are not categorical.