Biliary strictures (BS), a major complication after orthotopic liver transplantation (OLT), cause morbidity, mortality, graft loss, and increased costs. The virtually unchanged incidence of BS (approximately 10%-25%) suggests that they are not simply "technical" in origin, but probably represent a mucosa ischemic injury inherent in the transplantation procedure. To study risk factors for BS, we analyzed 403 OLTs performed between January 1, 1997 and December 31, 2006, at a single center, excluding cases of regraft or death within 1 month. The average time to the diagnosis of the BS was 253 days (range, 7-1002 days). Upon univariate analysis, the absence of flushing of donor bile ducts, an imported versus a locally procured liver, and rejection were risk factors for BS. In contrast, the following factors were protective: donor cardiac arrest followed by resuscitation (suggesting an ischemic preconditioning effect) as well as addition of epoprostenol to and pressurization of the preservation solution. Patients with higher postoperative peak values of transaminases, bilirubin, alkaline phosphatase, and gamma glutamyl transpeptidase were at greater risk for later development of BS. Donor hypotension, donor age, donor intensive care unit (ICU) stay, type of preservation, positive cross-match, cold and warm ischemia times, sequential versus simultaneous portal/arterial reperfusion, as well as cytomegalovirus (CMV) infection were not risk factors for BS. Upon multivariate analysis, only epoprostenol and pressurization offered protection from BS. In conclusion, this study 2 novel points: (1) patients with high(er) transaminase values and cholestasis early postoperatively are at greater risk to develop later BS and require close monitoring and (2) donor maneuvers for better flushing and preserving peribiliary vascular plexus and biliary mucosa (epoprostenol and pressurization of preservation solution) offer protection from BS.