The lipoprotein profile of patients with primary biliary cirrhosis (PBC) has been assessed by high performance liquid chromatography (HPLC). Without exception, all subjects with PBC had an abnormal high density lipoprotein (HDL), which was larger than normal HDL. The elution time from an HPLC column of the abnormal HDL separated it clearly from normal HDL. The HDL of subjects with asymptomatic and symptomatic PBC could also be distinguished. The HDL of asymptomatic subjects was eluted between that of normal and symptomatic subjects. The lipid and protein composition of abnormal HDL was characterized by an increase in phospholipid and a decrease in protein, resulting in an increase in the ratio of phospholipid/protein. This ratio was higher in symptomatic than in asymptomatic PBC. Incubation of dimyristoyl phosphatidylcholine liposomes with normal serum resulted in the formation of an altered high density lipoprotein. These findings suggest that an overload of phospholipid may play a role in the formation of the abnormal HDL in primary biliary cirrhosis.