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Orthotopic liver transplantation (OLT) is the treatment of choice for patients with end-stage primary sclerosing cholangitis (PSC). This study sought to chronicle the natural history of PSC recurrence following OLT and identify clinical variables that may contribute to disease reemergence. From 1988 to 2006, 1102 OLTs were performed in 1032 adults at the University of Colorado Health Sciences Center. Of these, 130 patients (12.6%) with PSC received 146 allografts. Recurrence was defined by a clinically worsening examination and radiographic evidence. A total of 9 potential predictors were considered, using both bivariate log rank and multivariate Cox analysis, including: age > 55, gender, surgical technique (piggyback technique), presence of inflammatory bowel disease, intact colon before transplant, or cholangiocarcinoma (CCA), cold ischemia time, sirolimus-based immunosuppression, and graft type. The 1, 5, and 10-year recurrence-free survival was 91%, 76%, and 61%, respectively. The crude incidence of disease recurrence was 22 of 130 patients or 16.9%. Patients' risk of recurrent PSC at 1, 5, and 10 years was 2%, 12%, and 20%, respectively (mortality censored). Of the 22 patients that developed recurrent disease, 7 received a second transplant. Of the 9 factors considered, the presence of CCA prior to OLT is significantly predictive of disease recurrence [risk ratio (RR) = 3.77; P = 0.0038]. Once a patient was diagnosed with recurrent disease, the median survival without receiving a second transplant was 39.1 months (95% confidence interval: 27.6-50.6 months). In conclusion, recurrent PSC following OLT is a formidable but protracted problem following OLT. Patients may require a second transplant following reemergent disease with reasonable survival benefit. Liver Transpl 14:181–185. 2008. © 2008 AASLD.