Background: No established medical therapy alters the progressive course of primary sclerosing cholangitis. Objective: To explore the potential usefulness of combined therapy with azathioprine, steroids and ursodeoxycholic acid (UDCA) in primary sclerosing cholangitis. Design: Case series. Setting: University hospital in Mainz, Germany. Patients: 15 patients with primary sclerosing cholangitis. Interventions: Azathioprine (1 to 15 mg/kg of body weight per day), prednisolone (1 mg/kg per day initially, tapering to 5 to 10 mg per day) and UDCA (500 to 750 mg per day). Measurements: Clinical and laboratory evaluation, liver biopsy, and endoscopic retrograde cholangiography (a >30% change in stenosis was considered significant). Results: After a median observation period of 41 months (range, 3 to 81 months), liver enzyme levels declined significantly in all patients. Six of 10 patients with follow-up liver biopsies showed histologic improvement. Significant radiologic deterioration was seen in only 1 of 10 patients who had endoscopic retrograde cholangiography. In 7 patients previously treated with UDCA alone, liver enzyme levels declined significantly only after immunosuppressive therapy was added. Adverse drug reactions led to the withdrawal of study medication in 2 patients. Conclusions: Combined immunosuppressive therapy may alter the progression of primary sclerosing cholangitis. Our observations suggest a benefit from adding immunosuppressive drugs to UDCA therapy. A randomized trial is warranted.