Severe liver disease may be associated with a reduction in plasma concentration of high density lipoprotein and an impairment of plasma cholesterol esterification. These changes were confirmed in two patients with severe acute on chronic alcoholic liver disease. In five additional patients with biopsy-proven clinically compensated cirrhosis, there wasminimal reduction in concentration of plasma cholesteryl esters; there was, however a reduction of the plasma high density lipoprotein concentration to only 48 to 66% of normal. The particle size distribution of high density lipoprotein in these five patients was determined by gradient gel electrophoresis. The high density lipoprotein2 subfraction was preserved. The high density lipoprotein3 subfraction, however, was markedly changed with a reduction in the normal particles of radius 4.3 m and an accentuation of smaller particles of radius 3.9 m; in two patients, these smaller particles were the major high density lipoprotein subpopulation. Further investigations of this finding of a distinctive distribution of high density lipoprotein subpopulations in patient with chronic liver disease may provide new insights into high density lipoprotein metabolism.