Background Circulating endothelial progenitor cells (EPCs) may play an important role in the body's defense against atherosclerosis. Previous studies have shown an association between EPC numbers and the presence of traditional coronary artery disease (CAD) risk factors. The relationship between EPC numbers and the severity of atherosclerosis is, however, not known. Methods EPC counts were measured by quantitative cell culture in 122 patients undergoing diagnostic cardiac catheterization. The association between patients' EPC count and the presence of multivessel CAD and traditional cardiac risk factors was assessed using logistic regression analysis. Results The median age of the study population was 58 years; 37% had multivessel CAD, 29% had diabetes, and 14% had myocardial infarction this admission. EPC counts did not vary significantly with most established cardiac risk factors but were lower in diabetics versus nondiabetics and trended toward lower numbers in older patients. EPC count was the second strongest predictor of multivessel CAD, after patient age. Patients with multivessel disease had significantly lower EPC counts than those without (median, 3 vs 13; P < .0088). For every 10 colony forming unit increase in EPCs, a patient's likelihood for multivessel CAD declined by 20% ( P < .001). Conclusion This study demonstrates an inverse relationship between circulating EPCs and CAD severity, independent of traditional risk factors. If confirmed in ongoing studies, this may represent an important new diagnostic and therapeutic target for coronary disease treatment.