Predictive factors for intrahepatic cholestasis after orthotopic liver transplantation (OLT) have not yet been established. We sought to identify the incidence and risk factors associated with prolonged severe intrahepatic cholestasis (PSIC) after OLT. We assessed 428 consecutive patients undergoing their first OLT. PSIC was diagnosed if a serum bilirubin concentration was greater than 100 micromol/L and/or a 3-fold increase of alkaline phosphatase occurred within the first month after OLT and was sustained for at least 1 week in the absence of biliary complications. Multivariable logistic regression identified factors independently associated with PSIC. PSIC developed in 107 patients (25%). Independent risk factors by multivariable analysis were intraoperative transfusion of cryoprecipitate and platelets; nonidentical blood group status; suboptimal organ appearance; inpatient status before transplantation; and bacteraemia in the first month after transplantation. In contrast, acute liver failure, older age, and higher levels of serum sodium and serum potassium were all associated with a reduced likelihood of developing PSIC in the first month. There were 47 deaths in the PSIC group (44%) as opposed to 65 deaths in the non-PSIC group (20%) after OLT. A poor preoperative clinical status in conjunction with a suboptimal graft was associated with PSIC after OLT. Avoidance of suboptimal livers and ABO nonidentical grafts for young patients with poor synthetic function and for pretransplant inpatients may lessen this complication and reduce the associated early mortality.