Background. Graft-versus-host disease (GVHD) is an important, underdiagnosed cause of mortality associated with liver transplantation. We identified 12 cases of GVHD among 1,082 liver transplantations performed in patients at our institution between 1991 and 1998. Patients typically developed fever, skin rash, diarrhea, or pancytopenia within 2 to 6 weeks after their transplant. Treatment generally involved increased immune suppression and hematopoietic cytokines (granulocyte colony stimulating factor, granulocyte monocyte colony stimulating factor); however, all but one patient died, most often from sepsis. Early in its course, GVHD was difficult to distinguish from cytomegalovirus disease or drug reactions. The diagnosis was confirmed by demonstration of substantial donor lymphoid chimerism. Methods. To identify risk factors for severe GVHD, a retrospective analysis was performed comparing index cases with the rest of the cases in our institutional experience. Results. Closely matched human leukocyte antigen recipients, those older than 65 years, and recipients with donors more than 40 years younger were at higher risk for GVHD. One case occurred in a patient with a congenital immunodeficiency. Conclusions. Liver transplant-associated GVHD is a progressive and fatal disease. Future approaches should focus on prevention and might include avoidance of closely matched human leukocyte antigen donors, treatment of the donor to reduce the number of lymphocytes, or reduction of immunosuppression in the early posttransplant period.