Approximately 15% of middle-aged Americans have primary hypercholesterolemia, that is, plasma cholesterol levels in excess of 250 mg/dl. The risk for coronary heart disease in these patients is at least twice that of patients with a baseline level of 200 mg/dl. Only 2% of hypercholesterolemic patients have familial hypercholesterolemia. The causes of elevated cholesterol concentrations in the remaining patients have not been determined. Three major mechanisms may be responsible: (1) overproduction of lipoproteins by the liver, (2) reduced activity of receptors for low-density lipoproteins (LDL), and (3) low affinity of circulating LDL for receptors. We have examined each of these mechanisms for primary hypercholesterolemia by isotope kinetic techniques. All three types have been identified, and the underlying causes of each are under investigation.