Chronic irreversible rejection is a major cause of graft loss and retransplantation after orthotopic liver allotransplantation. To identify risk factors we retrospectively analysed 423 adult consecutive primary liver allograft recipients. The endpoint of the study was graft failure due to chronic rejection leading either to retransplantation or death. Chronic rejection developed in 22 (5.2%) patients. Pretransplant diagnosis of primary biliary cirrhosis or autoimmune hepatitis, recipient age less than 30 years, 1 or more episodes of acute cellular rejection, and transplantation of an organ from cytomegalovirus (CMV). IgG positive donor to an IgG negative recipient were identified as risk factors for chronic rejection. Transplantation of a liver from a male donor into a female recipient was also associated with an increased probability of chronic rejection. By logistic regression analysis, the probability of chronic rejection was predicted by: sex and cytomegalovirus match of donor and recipient, the presence of acute rejection, recipient age, transplantation for autoimmune hepatitis or primary biliary cirrhosis, and recipients receiving no azathioprine during the third month after transplantation. Sensitisation to antigens expressed by bile-duct epithelium as in primary biliary cirrhosis or exposure to donor bile-duct minor histocompatibility antigens, such as the male sex related H-Y antigen, may provide an explanation. More selective allocation of donor organs may allow a reduction in the incidence of ductopaenic rejection and graft loss.