We retrospectively evaluated the association between risk factors and acute graft-versus-host disease (aGVHD) among 182 beta thalassemia patients who received 73 peripheral blood stem cell (PBSC) or 109 bone marrow transplants from HLA-identical siblings between 1991 and 2003. The relationship between the severity of aGVHD was examined for the following factors: HLA antigens, age, sex, ABO mismatch, sex mismatch (between recipient and donor), thalassemia class, graft source, transplant cell dose, CD3+ cell dose, conditioning regimen, GVHD prophylaxis, neutrophil engraftment duration, and blood product transfusions using univariate and multivariate analyses. Overall 61 (34%) patients developed clinical grade III or grade IV aGVHD. Univariate analysis confirmed an increased risk of severe aGVHD, which was associated with HLA-A11, HLA-A26, and PBSCT (P=.04, .03, and .03, respectively). The risk of aGVHD was reduced in the presence of HLA-A3 (P=.03). Multivariate analysis confirmed the increased risk of aGVHD associated with HLA-A11 (P=.04), HLA-A26 (P=.01), and a short-period neutrophil recovery (P=.009). In this study HLA-A11, HLA-A26, PBSCT, and a short neutrophil engraftment period were probable risk factors and HLA-A3 a probable protective factor associated with severe aGVHD. These data may provide useful guidelines to choose strategies for treatment and prevention.