We have shown that marked reduction of serum cholesterol and marked regression of cutaneous and tendon xanthomas were obtained by probucol treatment even in homozygous as well as heterozygous cases of familial hypercholesterolemia under low fat and low calory diet, although the treatment caused a remarkable decrease in HDL-cholesterol (Atherosclerosis 48, 157, 1983). In order to elucidate the mechanism of the effects of probucol, we investigated the relation between the extent of the regression of lipid storage evaluated by xeroradiography of Achilles tendon thickness and the changes in lipoproteins. The reduction of Achilles tendon thickness was not correlate with that of serum cholesterol, while it correlated closely with the extent of the reduction of HDL-cholesterol. High performance liquid chromatography of lipoproteins revealed that HDL2 particles from probucol-treated cases with familial hypercholesterolemia were small in size. In addition, net transfer rate of cholesteryl ester from HDL to larger particles was found to be enhanced by probucol treatment. These findings provide us the hypotheses that probucol may enhance cholesterol catabolism through the other pathway but LDL-receptors by stimulating the cholesterol transfer from HDL to larger lipoprotein particles and consequently may enhance the reverse transfer of Ch to take lipids out from the tissues.