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Acute cellular graft-vs.-host disease (GVHD) following liver transplantation has an incidence of 1 to 2% and a mortality rate of 85%. Our aim was to identify a patient population at high risk for developing GVHD using a large clinical database to study both recipient and donor factors. We compared our liver transplant patients who developed GVHD to those that did not for recipient and donor factors and combinations of factors. For 2003–2004 we had 205 first-time liver transplant patients surviving >30 days. From this group, 4 (1.9%) developed GVHD. Compared to the control group, there were no significant differences in recipient age, recipient gender, donor age, donor gender, total ischemia time, donor-recipient human leukocyte antigen (HLA) mismatch, or donor-recipient age difference. Percentages of liver disease etiologies among the patients who developed GVHD were as follows: 16% (1/6) autoimmune hepatitis (AIH) (P = 0.003), 5.6% (3/54) alcoholic liver disease (ALD) (P = 0.057), and 7.1% (3/42) hepatocellular carcinoma (HCC) (P = 0.026). The incidence of GVHD in patients with glucose intolerance (either Type I or Type II diabetes mellitus [DM]) was significant (P = 0.022). Focusing on patients only with high-risk factors for GVHD during the years 2003–2005, we had 19 such patients. Four of these high-risk patients developed GVHD. Three of these 4 patients had received a donor liver with steatosis of degree ≥mild compared to only 2 of the 15 high-risk patients who did not develop GVHD (P = 0.037). In conclusion, we have identified liver transplant patients with AIH or the combination of ALD, HCC, and glucose intolerance who receive a steatotic donor liver as being at high risk for developing GVHD. Liver Transpl 13:516–522, 2007. © 2007 AASLD.