Hematopoietic cell transplantation from unrelated volunteer donors for the treatment of hematological malignancy can be optimized by complete and precise matching for HLA class I and II alleles between the donor and recipient. Survival is improved when the donor and recipient are matched for HLA-A, -B, -C, -DRB, -DQB1 and -DPB1 alleles. The risks of clinically severe graft-versus-host disease, graft failure and mortality are increased in the presence of multilocus mismatching. These findings demonstrate that HLA allelic differences are biologically relevant in human transplantation.