In unrelated marrow transplantation, the benefit of matching class II HLA-DRB1 and DQB1 alleles of the donor and recipient is well documented. Little is known about the clinical relevance of matching for class I HLA-A, B, and C alleles. We used DNA-amplification methods to identify the HLA-A, B, and C alleles of 300 patients and their donors. The incidence of graft failure was correlated with multiple class I mismatching in the donor. The risk of grades III-IV acute graft-versus-host disease was highest with class II mismatching in the recipient. Mismatching for a single class I or class II allele had no effect on survival, but mortality was increased by mismatching for more than one class I allele and by simultaneous mismatching for class I and class II alleles. We conclude that matching HLA class I and class II alleles of the donor and recipient can improve outcome after unrelated marrow transplantation.