Irreversible ductopenic rejection (DR) after orthotopic liver transplantation (OLT) is a major cause of late hepatic allograft failure. A variety of risk factors for DR have been postulated, but they are controversial. All transplant recipients at our institution with graft survival of more than 1 month (n = 120) were examined retrospectively with a view to possible risk factors for DR. These factors included age, sex, underlying liver disease, hepatitis B and C infections, donor-recipient CMV status, post-OLT CMV infections, immunosuppressive regimen, ABO blood type, and HLA class I and class II mismatches. Statistical analysis was performed with the univariate chi-square test or the two-tailed Fischer's exact test. Ten patients (8.3%) developed DR. Seventeen patients had HCV infections after OLT. In this group, the incidence of DR was highest (4 of 17, or 23.5%). This was significantly higher than for all other OLT groups (6 of 103 patients, or 5.8%; P < 0.03). The other factors analyzed did not reach statistical significance, including those that other authors found important for the development of DR. It may well be that hepatitis C infection predisposes one to the development of DR after OLT.