Objective To investigate the risk factors of severe intrahepatic cholestasis during early period after liver transplantation. Methods The clinical data of 225 patients who received orthotopic liver transplantation at the Nanfang Hospital of Southern Medical University from August 2004 to February 2011 were retrospectively analyzed. All patients were divided into positive group (60 patients with intrahepatic cholestasis) and negative group (165 patients without intrahepatic cholestasis). Preoperative, intraoperative and postoperative factors of the 2 groups were compared via t test, chi square test, Wilcoxon test or Logistic regression analysis. Results The proportion of patients with hepatic cirrhosis, hepatic encephalopathy integral, ascites integral, international normalized ratio, and the levels of prothrombin time (PT), total bilirubin (TBil), aspartate aminotransferase of the positive group before operation were significantly higher than those in the negative group (χ 2=6.09, Z= 2.22, 2.60, 2.46, 2.84, 4.81, 3.42, P <0.05),while the levels of albumin, Na +, K +, hemoglobin, platelet (PLT) of the positive group in the operation were significantly higher than those in the negative group ( t=2.10, 4.97, Z=2.49, t=3.51, Z=3.66, P <0.05). The ratio of compatible blood type of the donors and recipients, ratio of fatty liver graft, cold ischemia time, relative warm ischemia time, intraoperative blood loss, intraoperative transfusion of red blood cells, PLT, and cryoprecipitate of the positive group after the operation were significantly higher than those in the negative group (χ 2=4.29, 13.11, Z=2.45, 2.61, 3.75, 3.20, 2.89, 3.95, P < 0.05) . The incidences of acute rejection, hepatic artery embolism, pulmonary infection, bacteraemia, fungal infection and cytomegalovirus (CMV) infection were significantly higher than those in the negative group (χ 2= 9.87, 4.91, 8.21, 6.29, 3.92, 9.26, P <0.05). The Results of multivariate analysis revealed that preoperative level of TBil>51.3 μmol/L, fatty of the liver graft, intraoperative transfusion of cryoprecipitate, postoperative acute rejection, hepatic artery embolism, postoperative pulmonary infection, bacteraemia, CMV infection were independent risk factors of severe inrahepatic cholestasis ( OR=15.82, 7.99, 2.88, 3.03, 53.20, 3.34, 4.11, 3.22, P <0.05). The incidence of severe intrahepatic cholestasis was significantly lower in patients with higher level of PLT and longer PT ( OR=0.33, 0.25, P <0.05). The mortality rates of the positive group and negative group at 6 months after the operation were 41.7%(25/60) and 19.4%(32/165), and the mortality rate of the positive group was significantly higher (χ 2=11.54, P <0.05). Conclusion Correction of poor clinical status before liver transplantation, reinforcement of infection control and anti rejection may reduce the incidences of complications and decrease the associated early mortality.