Background: Transfusion-associated graft-versus-host disease (TA-GVHD) due to blood from HLA-homozygous related and unrelated blood donors has been described. Case Report: Fatal TA-GVHD due to the transfusion of HLA-matched platelets from an unrelated HLA-homozygous donor is reported. A 61-year-old man with a history of diabetes mellitus and myelodysplastic syndrome was diagnosed with acute myelogenous leukemia in November 1991. Induction chemotherapy resulted in aplasia, which was followed by a normocellular marrow with mild dysplasia and continued karyotypic abnormalities. High-dose chemotherapy was given in a second attempt to achieve complete remission. HLA-matched platelets were ordered when platelet refractoriness developed. The patient was HLA-heterozygous for HLA-A and -B antigens (A2, 29; B37, 44). Over the next 7 days, four unirradiated HLA-matched plateletpheresis units were transfused; one was probably homozygous for both H LA-A and -B antigens (A2, -; B44, -) and was transfused first, and three were probably homozygous for an HLA-B antigen (A2, 29; B44, -) and were white cell reduced. No blood relatives served as donors. Seven days after the first HLA-matched platelet transfusion, fever, chills, and diarrhea developed; 2 days later, a rash was present. Liver enzymes increased markedly. Renal and respiratory failure ensued. A skin biopsy was consistent with GVHD. Despite immunosuppressive therapy, the patient died 19 days after the first HLA-matched platelet transfusion. Conclusion: TA-GVHD has been recognized in immunocompromised, HLA-heterozygous patients receiving blood from blood relatives who are HLA-homozygous. It has also been recognized in immunocompetent, HLA-heterozygous patients receiving blood from either blood relatives or non-blood relatives who are HLA-homozygous. This HLA-heterozygous patient received transfusions of unirradiated, class I HLA-homozygous platelets, which were specifically ordered as HLA-matched, and his death was attributed to TA-GVHD. Consideration should always be given to providing irradiated blood for immunosuppressed patients, especially when HLA-matched platelets are used, to prevent TA-GVHD.