Plasmapheresis was studied as a means of reducing the serum cholesterol concentration in 3 hypercholesterolemic patients who each underwent courses of intensive plasmapheresis with removal of 250--500 ml of plasma each day for 5--9 days. In one homozygous Type II patient, the serum cholesterol concentration decreased from 609 +/- 45 mg/100 ml (mean +/- SEM) to 365 +/- 17 mg/100 ml (40% decrease, P less than 0.05) with two different courses of plasmapheresis. In the two other patients with non-homozygous hyperbetalipoproteinemia the serum cholesterol concentration decreased from 289 +/- 27 mg/100 ml to 205 +/- 19 mg/100 ml (29% decrease, p less than 0.05). After cessation of treatment, the cholesterol concentration returned to pre-treatment levels in 10--13 days in the homozygous patient and 7 days in one non-homozygous hyperbetalipoproteinemic patient; clofibrate (2 g/day) in this patient was associated with a smaller reduction of the cholesterol concentration with plasmapheresis and an increased rate of return of pre-treatment levels after plasmapheresis was stopped. Sustained plasmapheresis for 6 days in the other non-homozygous hyperbetalipoproteinemic patient resulted in a new approximate "steady state" with a serum cholesterol concentration of 176--199 mg/100 ml compared with a pre-plasmapheresis value of 227 mg/100 ml. The response of the plasma cholesterol levels to plasmapheresis was subjected to kinetic analysis based on a current model of the regulation of lipoprotein metabolism.