Although one-way matching between an HLA-homozygous donor and a haploidentical recipient is a recognized risk factor in transfusion-associated graft-versus-host disease (GVHD), its impact in living-related liver transplantation (LRLT) has so far not been investigated. We present a case of fatal acute GVHD in our LRLT program that was attributed to one-way HLA matching between donor and recipient. Although the disappearance of donor cells in peripheral blood was suggested by genetic analysis, severe septicemia led to a fatal outcome. We further reviewed 280 LRLT cases and correlated one-way HLA matching with outcome. A total of 8 out of 280 donors (2.9%) and 11 out of 278 recipients (4.0%) were completely HLA homozygous in our LRLT program. Complete one-way HLA matching linked to GVHD was observed in four cases, including the present case. Although other contributing factors also need to be clarified, one-way HLA matching is a definite risk factor for GVHD in LRLT. We advocate caution before proceeding with one-way HLA donor-recipient combinations.