No effective medical therapy is currently available for primary sclerosing cholangitis (PSC). Ursodeoxycholic acid (UDCA) improves liver enzymes, but its effect on liver histology is controversial. Metronidazole (MTZ) prevents PSC-like liver damage in animal models and reduces intestinal permeability. We recruited 80 patients with PSC into a randomized placebo-controlled study to evaluate the effect of UDCA and MTZ (UDCA/MTZ) compared with UDCA/placebo on the progression of PSC. Patients (41 UDCA/placebo and 39 UDCA/ MTZ) were followed every third month. Assessment of liver function test, histological stage and grade, and cholangiography (via ERCP) at baseline showed no differences between the groups. After 36 months, serum aminotransferases ␥-glutamyltransferase, and alkaline phosphatase (ALP) decreased markedly in both groups, serum ALP more significantly in the UDCA/MTZ group (؊337 ؎ 54 U/L, P < .05) compared with the UDCA/placebo group. The New Mayo Risk Score decreased markedly only in the UDCA/MTZ group (؊0.50 ؎ 0.13, P < .01). The number of patients with improvement of stage (P < .05) and grade (P < .05) was higher in the combination group. ERCP findings showed no progression or improvement in 77% and 68% of patients on UDCA/MTZ and UDCA/placebo, respectively. In conclusion, combining MTZ with UDCA in PSC improved serum ALP levels and New Mayo Risk Score, but no statistically significant effect on disease progression as assessed via liver histology or ERCP was seen. Long-term studies using a higher dose of UDCA combined with MTZ in larger patient populations are indicated. (HEPATOLOGY 2004;40:1379 -1386.) P rimary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease of unknown etiology characterized by inflammation and fibrosis of the intraand extrahepatic bile ducts. 1 Approximately 80% of patients have concomitant inflammatory bowel disease, most commonly ulcerative colitis. The strong association between PSC and inflammatory bowel disease has been speculated to cause increased translocation of colonic bacteria and endotoxins, as well as enhanced absorption of toxic bile acids to the liver via the portal vein. 1,2 This may lead to activation of Kupffer cells in the liver, with consequent overproduction of tumor necrosis factor and immunoactivation of biliary epithelial cells in genetically susceptible patients. 2,3 A close genetic association of PSC with HLA-DR3, DQ2 has been reported 4 and is described in other autoimmune liver diseases, as well. 5 Moreover, in PSC biliary epithelial cells have demonstrated strong immunostaining for endotoxin. 6 In rats, overproduction of tumor necrosis factor has been associated with bile duct destruction and proliferation, 7,8