Graft-versus-host disease (GVHD) after liver transplantation is uncommon and the outcome is often fatal. A firm diagnosis of GVHD is difficult because the clinical triad of skin rash, marrow failure and diarrhoea can be indistinguishable from drug reaction or viral infection, and the presence of donor lymphocyte chimerism is not specific. We describe a case of severe GVHD in a female patient after liver transplantation from a male cadaveric donor. Skin biopsy showed characteristic changes of GVHD. Using Y-chromosome-specific fluorescent in situ hybridisation (FISH), male lymphocytes were demonstrated in 10% of marrow cells and in 90% of lymphocytes infiltrating the dermal–epidermal junction. Donor human leucocyte antigens (HLAs) were detected in the peripheral blood, buccal mucosa and skin by polymerase chain reaction. The GVHD subsided with steroid and anti-thymocyte globulin, but recurred on tailing off of treatment. Despite maximum supportive therapy, including random donor leucocyte infusion, and marrow infusion from a HLA-identical sibling, the patient succumbed to sepsis. Our results showed the utility of combining morphological features with molecular techniques using FISH and HLA typing in confirming a diagnosis of GVHD.