The nature and etiology of plasma lipoprotein abnormalities in patients with varying stages of primary biliary cirrhosis (PBC) were assessed. Two distinct lipoprotein patterns were observed. In patients with early and intermediate histologic stages of PBC, mild elevations of very low density lipoproteins and low density lipoproteins (LDLs), and marked increases in high density lipoproteins (HDLs) were often noted (group 1). In contrast, patients with advanced disease had marked elevations in LDLs with the presence of lipoprotein-X, and a significant decrease in HDLs (group 2). The lipoprotein pattern in group 1 was characterized by a normal ratio of free cholesterol to total cholesterol, whereas in group 2, this ratio was elevated. In plasma from group 1 patients only spherical micelles were observed on electron microscopy, whereas in plasma from group 2 patients bilayered disks could be seen in LDLs and HDLs. The increase in HDLs observed in group 1 subjects was associated with elevations in HDL2, whereas in group 2 subjects only very low amounts of HDL3 were observed on analytic ultracentrifugation. Mean plasma apolipoprotein B and C-II concentrations were increased in both groups; but apolipoprotein A-I and AII values were divergent, with group 1 subjects having elevated values,and group 2 subjects having decreases values. Mean postheparin hepatic lipase activity was decreased in both groups of patients with PBC due to the presence of an inhibitor in PBC plasma, while altered cholesterol esterification was only observed in group 2. These data indicate that hepatic lipase inhibition may play an important role in the pathogenesis of the lipoprotein abnormalities seen in early and intermediate PBC, and these abnormalities are then further modified by altered cholesterol esterification in advanced disease.