Primary sclerosing cholangitis (PSC) is the fourth leading diagnosis in liver transplant recipients in the United States. The disease is known to recur in 15% to 30% of liver transplant recipients. We set out to investigate how different immunosuppression regimens affected natural history of PSC after liver transplantation at our center. We reviewed records of all patients who underwent a liver transplantation at our institution in between 1988 and 2000 and had a diagnosis of PSC at the time of liver transplantation. Primary sclerosing cholangitis recurred in 15 of 71 patients (21.1%) who had complete records and survived more than 30 days after liver transplantation. Although recurrence of primary sclerosing cholangitis was most often seen (but not statistically significantly so) in patients who received maintenance corticosteroids, the time to recurrence was not significantly different between those who were treated with maintenance, those who were not successfully weaned, and those who successfully weaned off corticosteroids within 3 months after liver transplantation. Orthoclone (OKT3) therapy (Ortho-Biotech, Inc., Raritan, NJ) was associated with a higher risk of primary sclerosing cholangitis recurrence (29% versus 10%, P <.05). Recurrence was not influenced by immunosuppression with either cyclosporine or tacrolimus. Coexistent inflammatory bowel disease was a cause of failure to wean off corticosteroids, was associated with a shorter time to recurrence of sclerosing cholangitis, and was responsible for significant comorbidity (colon cancer in 7.3%). Primary sclerosing cholangitis recurrence is commonly seen after liver transplantation. More immunosuppression seems to be detrimental to the outcome of our patients with sclerosing cholangitis: use of OKT3 was associated with a greater incidence of recurrence. Length of corticosteroid use did not affect timing or risk of recurrence, and because it has been proven that early corticosteroid withdrawal after liver transplantation is beneficial, we continue to recommend this practice.