To analyze and evaluate the clinical effect of ABO-incompatible liver transplantation in the treatment of acute severe liver disease. A retrospective clinical study was conducted. The clinical data of 4 136 patients undergoing orthotopic liver transplantation in Organ Transplantation Center of Tianjin First Center Hospital from September 1999 to December 2013 were analyzed. The criteria of patients enrolled were as following: model for end-stage liver disease (MELD) score ≥ 20, the donor's and recipient's blood types were different, age 18-70 years, and undergone primary non-bypass orthotopic liver transplantation. According to the rate of compliance with the principles of blood transfusion, the cases were divided into two groups: ABO-compatible group (ABO-C group, n=41), ABO-incompatible group (ABO-I group, n=22). The patients in ABO-I group received basiliximab + methylprednisolone for immune induction therapy during operation, basiliximab + tacrolimus + mycophenolate + cortisol as quadruple immunosuppressive regimen after operation. They also received subcutaneous injection of low molecular heparin for anticoagulant therapy after operation, and oral warfarin or aspirin and clopidogrel bisulfate instead after 7 days. They also received routine alprostadil after operation. The remaining treatment was the same as that of ABO-C group. The clinical data, postoperative complications, rejection and survival rates of two groups were statistically analyzed. There were no significant differences in gender, age, MELD score, complicated with tumor, quality of donor liver, length of cold preservation of donor liver, duration of operation, and blood loss during operation between ABO-C and ABO-I groups. Number of splenectomy during operation was significantly higher in ABO-I group than that in ABO-C group (5 cases vs. 1 case, χ² = 4.687, P=0.030). The 3-month, 6-month, 1-year, 3-year and 5-year survival rates of ABO-C group were 89.5%, 78.3%, 72.5%, 69.1% and 61.8%, respectively, while those of ABO-I group were 78.9%, 72.9%, 65.6%, 56.2% and 46.8%, respectively. There was no significant difference in the cumulative survival rate between two groups (Log Rank, χ² = 0.647, df=1, P=0.421). The postoperative infection rate in ABO-I group was significantly higher than that of ABO-C group [63.6% (14/22) vs. 31.7% (13/41), χ² = 5.960, P=0.015]. There were no significant difference in postoperative complications of biliary tract [22.7% (5/22) vs. 12.2% (5/41), χ² = 0.531, P=0.466], vascular complications [31.8% (7/22) vs. 12.2% (5/41), χ² = 2.416, P=0.120], or rejection as diagnosed by pathology [22.7% (5/22) vs. 9.8% (4/41), χ² = 1.051, P=0.305] between ABO-I and ABO-C groups. Although ABO-incompatible liver transplantation was followed by higher postoperative infection rate and perioperative mortality, ABO-incompatible liver transplantation can still be used to save the patient with acute severe liver disease as there is a shortage of compatible donor at present.