Human leukocyte antigen (HLA) DR15 is associated with autoimmune cytopenia in patients with aplastic anemia, myelodysplastic syndrome, and paroxysmal nocturnal hemoglobinuria. Presence of this antigen also predicts response to immunosuppressive treatment. If DR15 expression on hematopoietic cells also favors induction of immune responses in an allogeneic setting, a lower relapse rate after hematopoietic stem cell transplantation (HSCT) might result through an enhanced graft-versus-leukemia effect. We retrospectively analyzed outcome of HLA-identical sibling HSCT in 192 consecutive patients with acute or chronic leukemia or non-Hodgkin lymphoma. Patients carrying the DR15 antigen had a higher estimated 5-year overall survival (76%) than did DR15-negative patients (55%; P = .04). Improved survival for DR15 patients was due to a significant decrease in death from relapse (5% for DR15(+) versus 24% for DR15(-); P = .02), whereas no difference was seen for rates of transplant-related mortality (19% and 21%, respectively; P = .76). Findings were confirmed by multivariate analyses. Our results show an association of DR15 with a decreased risk of disease relapse and improved survival after HSCT for leukemia or non-Hodgkin lymphoma. This adds to the growing list of links between DR15 and immune reactions in hematopoiesis.