Transfusion-associated graft-versus-host disease (TA-GVHD) may occur in transfusions of blood from HLA-homozygous persons to HLA-heterozygous persons who share a haplotype. Two mathematical models were developed to calculate the upper and lower limit of the associated risks in various populations using a combination of serology- and DNA sequence-based HLA haplotype frequencies. For nondirected transfusion, the range of the estimated risk in United States whites is 1 of 17,700 to 39,000 (1/6,900-48,500 in Germans; 1/1,600-7,900 in Japanese). The risk in directed donation between parents and children is increased at least 21-fold for US whites, 18-fold for Germans, and 11-fold for Japanese. For nondirected transfusions, the estimates of TA-GVHD risk derived in this model are lower than estimates of previously published models, are in better agreement with the clinical experience, and explain in part the observed discrepancy between TA-GVHD incidence in the United States and that in Japan. Most notably for US whites, the relative increase in risk in directed transfusion is larger than previously thought.