The use of algorithms such as HLAMatchmaker to redefine donor-recipient HLA matching is gaining increasing attention. Our research has previously demonstrated that higher HLA class II eplet mismatches correlated with the development of chronic lung allograft dysfunction (CLAD). In this study of lung transplant recipients we prospectively examined the association between donor-recipient HLA eplet mismatches as defined by HLAMatchmaker (version 2.1) and de-novo anti-HLA donor-specific antibody (DSA) formation, as assessed by single antigen-bead solid phase assay. HLA class II eplet mismatch, when split at the median for the cohort, predicted the development of de-novo HLA class II DSA at 3 months but not at 12 months. Having previously shown that high HLA class II eplet mismatches was associated with CLAD, we now show that the same factors are associated with de-novo HLA class II DSA post-transplant.