Ursodeoxycholic acid (UDCA) has beneficial effects in cholestatic liver diseases. In primary sclerosing cholangitis (PSC), there is evidence that high doses (ุ20 mg/kg) of UDCA may be more effective than average doses. Biliary enrichment of UDCA at such high doses may represent the decisive factor for its beneficial effect. Up to now it is not clear how high-dose UDCA correlates with its biliary enrichment and whether bacterial degradation of large amounts of UDCA may lead to an increased bacterial formation of more toxic hydrophobic bile acids. We determined the biliary bile acid composition in 56 patients with PSC including 30 patients with repeat bile samples treated with various doses of UDCA. At a UDCA dose of 10 -13 mg/kg/d (n โซุโฌ 18) biliary UDCA represented 43.1% ุ 0.3% (mean ุ SD) of total bile acids; at a UDCA dose of 14 -17 mg/kg (n โซุโฌ 14), its biliary content increased to 46.9% ุ 0.3%, at 18 -21 mg/kg (n โซุโฌ 34) to 55.9% ุ 0.2%, at 22-25 mg/kg (n โซุโฌ 12) to 58.6% ุ 2.3%, and at 26 -32 mg/kg (n โซุโฌ 8) to 57.7% ุ 0.4%. During UDCA treatment, the biliary content of all other bile acids was unchanged or decreased. In conclusion, biliary enrichment of UDCA increases with increasing dose and reaches a plateau at 22-25 mg/kg. There was no increase of toxic hydrophobic bile acids. If biliary enrichment of UDCA represents the decisive factor for its clinical effect, it seems likely that UDCA doses of up to 22-25 mg/kg may be more effective than lower doses. (HEPATOLOGY 2004;40:693-698.) U rsodeoxycholic acid (UDCA) has beneficial effects in cholestatic liver diseases. In primary biliary cirrhosis, UDCA treatment slows progression of the disease and improves survival. [1][2][3][4][5][6] In primary sclerosing cholangitis (PSC), UDCA improves laboratory parameters, [7][8][9][10][11][12] and its effect on the outcome is currently being evaluated. There is evidence 11,12 that high doses (ี20 mg/kg/d) of UDCA may be more effective than average doses (15 mg/kg/d). The biliary enrichment of UDCA, which may represent the key factor for its beneficial effect, 13 has not been studied at such high doses. The intestinal absorption of UDCA is incomplete 14,15 and the bacterial degradation of unabsorbed UDCA in the intestine may affect its own biliary enrichment and that of other bile acids. 16,17 The aim of the present study was to determine the optimal dose of UDCA with respect to its biliary enrichment.