C4b binding protein (C4bp) is a regulator of the classical pathway of the complementing system. It forms a complex with protein S which serves as a cofactor of coagulation inhibitor, protein C. We have reported that C4bp is an acute phase reactant and associated with total cholesterol and triglyceride concentrations (Biochim. Biophys. Acta 963 (1988) 98-108). This suggests a possible association of C4bp with athero-sclerosis. We examined the relation of C4bp levels and the severity of atherosclerosis of the descending thoracic aorta in 98 Japanese men. The severity of aortic atherosclerosis was assessed by average sclerotic length (ASL) and average sclerotic area (ASA), using transesophageal echocardiography. After adjustment for age, C4bp levels increased significantly with increasing ASL and ASA. The association remained significant even after adjusting for total cholesterol, hypertension, smoking, drinking, body mass index, fasting blood sugar, and uric acid. Immunohistochemical analysis of specimens of the descending thoracic aorta from autopsies, demonstrated the presence of C4bp in the foamy macrophages of fatty streaks and the necrotic core of atheromatous plaque. These findings indicate that the serum level of C4bp can serve as an independent indicator of aortic athero-sclerosis.