We examined current outcomes of unrelated donor allogeneic hematopoietic cell transplantation (HCT) to determine the clinical implications of donor-recipient HLA matching. Adult and pediatric patients who had undergone first myeloablative unrelated bone marrow or peripheral blood HCT for AML, ALL, CML, or MDS between 1999 and 2011 were included. All had high resolution typing for HLA-A, -B, -C, -DRB1. Of the total (n=8,003), cases were 8/8 (n=5,449), 7/8 (n=2,071), or 6/8 (n=483) matched. HLA mismatch (6-7/8) conferred significantly increased risk for grade II-IV and III-IV acute graft vs. host disease (GVHD), chronic GVHD, transplant-related mortality (TRM), and overall mortality compared to HLA matched cases (8/8). Type (allele/antigen) and locus (HLA-A, -B, -C, -DRB1) of mismatch were not associated with overall mortality. Among 8/8 matched cases, -DPB1 and -DQB1 mismatch resulted in increased acute GVHD, and -DPB1 mismatch had decreased relapse. Non-permissive -DPB1 allele mismatch was associated with higher TRM compared to permissive -DPB1 mismatch or -DPB1 match, and increased overall mortality compared to permissive -DPB1 mismatch in 8/8 (and 10/10) matched cases. Full matching at HLA-A, -B, -C, -DRB1 is required for optimal unrelated donor HCT survival, and avoidance of non-permissive -DPB1 mismatches in otherwise HLA-matched pairs is indicated.