Heparin cofactor II (HCII), a single chain glycoprotein with a MW of 65kDa, is a serine protease inhibitor that is synthesized by the liver and circulates in plasma. Heparin cofactor II inhibits thrombin by formation of a stable bimolecular complex, but has no activity against other proteases involved in coagulation or fibrinolysis. The rate at which HCII inhibits thrombin increases more than 1000-fold in the presence of heparin, heparan sulfate, or dermatan sulfate. Heparin cofactor II is unique among serine protease inhibitors in its ability to be stimulated by dermatan sulfate, and it binds to a minor subpopulation of dermatan sulfate oligosaccharides. Turnover studies of labeled HCII in humans suggest that 40% of the protein equilibrates with an extravascular compartment, but the distribution of HCII in various tissues has not been thoroughly investigated. Heparin cofactor II has been detected in the intima of normal human arteries, and the ability of dermatan sulfate in the arterial wall to stimulate HCII is decreased in atherosclerotic lesions.