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. INTERVENTION: Azathioprine (1 to 1.5 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 radiographic 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 medications 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.