OBJECTIVE In a subgroup of patients, primary sclerosing cholangitis (PSC) is complicated by high-grade focal strictures of the bile ducts, and this can have an unfavorable influence on the natural course of the disease. The aim of this study was to evaluate the efficacy and safety of endoscopic treatment in this selected patient group. METHODS Twelve symptomatic patients with primary sclerosing cholangitis and major ductal strictures were included in a prospective study of endoscopic treatment. All patients were managed by repeated angioplasty-type balloon dilation and nasobiliary catheter perfusion. A minimum of two treatment sessions was used, and therapy was continued until satisfactory reopening of the strictures was obtained. Routine endoscopic follow-up was performed after three, six, 12, 18, and 24 months, and then at yearly intervals. The efficacy of therapy was assessed by evaluating clinical symptoms, laboratory data, and cholangiograms. RESULTS The long-term follow-up averaged 23 months (range: 12-50 months). Two to nine (mean: three) treatment sessions were required to obtain satisfactory reopening of major biliary strictures. Eight patients showed considerable and sustained improvement. The mean serum bilirubin, alkaline phosphatase, gamma-glutamyl-transpeptidase, and alanine aminotransferase levels felt significantly by 73% (P = 0.0164), 46% (P = 0.0022), 55% (P = 0.0022), and 58% (P = 0.0022), respectively. The average radiographic stricture score before treatment was 3.2 +/- 0.8 (P = 0.0033). Three patients required liver transplantation seven, 12, and 40 months after the initiation of endoscopic treatment, due to a deterioration in hepatic function or an inability to exclude complex biliary malignancy. No major procedure-related side effects were observed. CONCLUSIONS Our results suggest that the endoscopic treatment of PSC patients with dominant bile duct strictures is effective, safe, and well-tolerated. However, it is important not to overlook the potential development of cholangiocarcinoma.