Current available data confer to HLA mismatch (6-7/8) a significant increased risk for grades II to IV and III to IV acute graft versus host disease, chronic graft versus host disease, transplant-related mortality (TRM) and overall mortality compared with HLA-matched cases (8/8). However, it is not yet clear if type (allele/antigen) and locus (HLA-A, -B, -C, and -DRB1) of mismatch are associated with overall mortality. In order to improve the outcome of the unrelated HSCT, many efforts are ongoing for identifying permissive and non permissive HLA disparity both for I and II classes HLA. Recently, several authors have highlighted the crucial role of allelic mismatching Cw combinations in supporting GVL/ graft versus host disease effect with a consequent decreased risk of relapse (p<0.003). On the contrary, Cw disparities as Cw03:03 vs Cw03:04 or Cw07:01 vs Cw07:02 seem to be permissiveness in terms of HSCT clinical outcome. Contemporarily, Japanese meta-analysis on 6967 unrelated HSCT has shown that the presence of HLA-B*51:01 in the donor/recipient pairs is associated with acute graft versus host disease not only for the strong linkage disequilibrium of HLA-C*14:02 and -B*51:01 but also for the effect of HLA-B*51:01 itself. Based on these data, mismatched HLA-C*14:02 should be considered a non-permissive HLA-C mismatch in donor selection because it seems to be a potent risk factor for severe acute graft versus host disease and mortality.