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Significant amounts of ursodeoxycholic acid (UDCA) used for the treatment of patients with primary biliary cirrhosis (PBC) become epimerized at C-3 to isoUDCA. We investigated the metabolism of isoUDCA and a possible pharmacologic effect in five patients (51.4 ± 5.8 years old; 3 females, 2 males) with PBC and persistent elevations of γ-glutamyl transpeptidase (γ-GT) and alkaline phosphatase despite treatment with UDCA for more than one year. Serum samples were analyzed for bile acid metabolites and surrogate markers of cholestasis in 4-week intervals after 1 g/d UDCA, wash-out, 0.5 g/d isoUDCA, 0.75 g/d isoUDCA, 0.75 g/d UDCA, and two further periods with 1 g/d UDCA. Bile acids in urine were analyzed after wash-out, 0.5 and 0.75 g/d isoUDCA, and 0.75 and 1 g/d UDCA. During wash-out, AST, AP, and γ-GT rose significantly (P < 0.05) but reversed to previous levels during the first isoUDCA period, with 0.5 g/d only. No further improvements were observed after increasing the dose of isoUDCA or switching back to UDCA. In serum, the relative amounts of isoUDCA and UDCA were 8.1 ± 7.4% and 16.2 ± 6.4% during 0.5 g/d isoUDCA, 6.2 ± 2.5% and 45.0 ± 4.1% during 0.75 g/d isoUDCA, and 0.5–3% and 56.4–60.0%, respectively, during UDCA. In urine, UDCA was the predominant bile acid both during isoUDCA and UDCA medications. The similar serum enrichment and urinary excretion of UDCA during administration of either isoUDCA or UDCA together with low concentrations of the intermediate of isomerization, 3-dehydro-UDCA, indicate a first-pass epimerization of isoUDCA to UDCA in the liver. Approximately 25% of serum isoUDCA and 10% of serum UDCA were conjugated with either glucuronic acid or N-acetylglucosamine, indicating hepatic formation and systemic secretion of glycosidic conjugates.In PBC patients, isoUDCA becomes isomerized to UDCA and has similar effects on surrogate markers of cholestasis. Thus, isoUDCA has pro-drug characteristics.