Osteoprotegerin (OPG) regulates osteoclast and immune functions and appears to represent a protective factor for the vascular system. However, the role of OPG in human atherosclerosis has not been evaluated. In this study, we assessed OPG serum levels in 522 age-matched men who, on the basis of coronary angiography, had either absence of coronary artery disease (CAD) or presence of single-vessel disease, double-vessel disease, or severe triple-vessel disease. OPG serum levels were positively correlated with age (r = 0.28; P < 0.001) and were higher in men with diabetes mellitus (P < 0.01). OPG serum levels in men without CAD were 5.4 +/- 2.0 pmol/liter, compared with 6.1 +/- 2.1 pmol/liter in single-vessel disease (P < 0.005), 5.9 +/- 2.4 in double-vessel disease (P < 0.05), and 6.3 +/- 2.3 pmol/liter in triple-vessel disease (P < 0.001). Moreover, OPG serum levels were positively correlated with the severity of CAD as determined by a CAD scoring system (r = 0.17; P < 0.01). In conclusion, our data underline that OPG serum levels are associated with the severity of CAD and are increased in elderly men and patients with diabetes mellitus. We conclude that increased OPG serum levels may reflect advanced cardiovascular disease in men.