Aberrant hepatic expression of HLA molecules has been shown to be present in primary biliary cirrhosis and may play a determining role in the pathogenesis of the disease. We have studied the effect of the long-term administration of ursodeoxycholic acid on hepatic HLA expression. Nine untreated patients with primary biliary cirrhosis, eight patients treated for at least a year with ursodeoxycholic acid and eight control subjects without hepatobiliary disease were compared. HLA expression was studied on liver biopsy sections using a direct immunofluorescence technique with specific monoclonal antibodies directed against class I or class II HLA molecules. Aberrant biliary HLA class II expression was not modified by chronic administration of ursodeoxycholic acid. In contrast, aberrant hepatocyte HLA class I expression was markedly reduced. Reduction in HLA class I expression may lead to decreased cytotoxic T cell-dependent lobular necrosis, which is thought to contribute to the progression of primary biliary cirrhosis to advanced stages. These findings suggest that the beneficial effect of ursodeoxycholic acid treatment in primary biliary cirrhosis could result not only from a reduction in the intrahepatic accumulation of cytotoxic bile acids but also from a reduction in immunological injury.