We compared the transfer of H-3-labeled cholesterol from high density lipoproteins isolated from subjects with hypoalphacholesterolemia (HDLhypo) and normolipidemia (HDLnorm) to human hepatoma Hep G2 cells, as well as the association (binding plus internalization) of I-125-labeled HDLhypo and I-125-labeled HDLnorm with the membranes of these cells. When lipoproteins were added at an equal protein concentration, [H-3]cholesterol was transferred into Hep G2 cells less intensively as compared with HDLnorm although the association of HDLhypo with the cells was more efficient. It is concluded that in hypoalphacholesterolemia the transfer of cholesterol from HDL to Hep G2 cells is reduced. This may be one of the reasons for the accelerated development of atherosclerosis in hypoalphacholesterolemic subjects.