Serum bile acid levels and distributions were studied every 6 mo in patients with primary biliary cirrhosis who were randomly assigned to receive ursodeoxycholic acid (13 to 15 mg/kg/day) (n = 73) or a placebo (n = 73) over a 2-yr period. In the ursodeoxycholic acid group, ursodeoxycholic acid was the predominant serum bile acid at 6 mo and throughout the 2-yr treatment period. The total concentration of endogenous bile acids decreased with a reduction in cholic acid (in the ursodeoxycholic acid group and the placebo group, respectively [mean +/- S.E.]: 13.0 +/- 2.2 and 12.6 +/- 2.5 mumol/L at entry vs. 3.5 +/- 0.6 and 9.0 +/- 2.2 mumol/L at 2 yr; p < 0.002), chenodeoxycholic acid (in the ursodeoxycholic acid group and the placebo group, respectively: 12.1 +/- 1.7 and 12.7 +/- 2.3 mumol/L at entry vs. 5.8 +/- 0.8 and 10.7 +/- 2.2 mumol/L at 2 yr; p < 0.02) and 3 beta-hydroxy-delta 5-cholenoic acid. The concentration of deoxycholic acid did not change, whereas that of lithocholic acid increased significantly (in the ursodeoxycholic acid group and the placebo group, respectively: 0.63 +/- 0.06 and 0.81 +/- 0.12 mumol/L at entry vs. 1.26 +/- 0.12 and 0.90 +/- 0.15 mumol/L at 2 yr; p < 0.001). These changes were independent of the histological stage of the disease. Thus during ursodeoxycholic acid administration the liver was exposed to a lower level of endogenous bile acids and to an increased concentration of ursodeoxycholic acid.(ABSTRACT TRUNCATED AT 250 WORDS)