The DR15 allele at the HLA DRB1 locus is a marker for immune-mediated bone marrow failure syndromes. We hypothesized that HLA DR15 plays a role in T-cell interactions with hematopoiesis and investigated the role of HLA DR15 on graft-versus-host disease (GVHD) and graft-versus-leukemia effects in HLA-matched allogeneic blood or marrow transplantation (BMT) performed for myeloid malignancies. We performed a retrospective analysis of 119 consecutive related and 48 consecutive unrelated allogeneic BMT for myeloid malignancies treated between 1991 and 2005 to investigate the influence of HLA DR15 on overall survival (OS), progression-free survival (PFS), and incidence of grades II to IV acute GVHD. HLA DR15 was determined by either molecular (n = 108) or serologic (n = 59) methods. The incidence of HLA DR15 was similar to the general white population (35/167 = 21%). There were no significant differences in transplantation characteristics between the HLA DR15-positive and -negative groups. There was no significant difference in chronic GVHD, OS, or PFS between the HLA DR15-positive versus-negative groups in any disease or donor relation subgroups. The HLA DR15-positive group experienced a significantly lower incidence of acute GVHD grades II to IV: 23% versus 42% (P = .041). These results suggest that HLA DR15 reduces the risk of acute GVHD.