Acute and chronic antibody-mediated rejection (ABMR) continue to be major problems undermining the success of kidney and other solid organ transplants. Cellular and molecular mechanisms underlying these pathologies remain largely unclear. Dysregulated donor-specific antibody (DSA) responses are induced in B6.CCR5-/- mice transplanted with complete MHC mismatched A/J kidney allografts and are required for rejection of the grafts. Acute ABMR of kidney allografts in B6.CCR5-/- recipients also requires myeloid and NK cell activation to express pro-inflammatory effector functions within the graft. This study tested the role of myeloid cell functions on NK cell activation and on allograft survival during ABMR by using recipients deficient in the myeloid cell-derived enzyme myeloperoxidase (MPO). A/J kidneys transplanted to B6.CCR5-/- recipients rejected between days 18-25 with histopathology of acute ABMR whereas A/J allograft rejection in B6.CCR5-/-MPO-/- recipients occurred between days 46-54 with histopathological and molecular features of chronic graft injury. On day 15, allograft-infiltrating NK cell activation to proliferate and express CD107a was markedly decreased in B6.CCR5-/-MPO-/- recipients and was accompanied by decreased graft expression of NK cell activation genes, including SH2D1B1, and IFN-g and the monocyte/macrophage chemoattractant CCL2. NanoString analysis of RNA from isolated NK cells infiltrating allografts in CCR5-/- vs. B6.CCR5-/-MPO-/- recipients on day 14 post-transplant indicated completely different transcriptomes, including integrin activation and matrix degradation pathways that were markedly decreased in graft infiltrating NK cells in B6.CCR5-/-MPO-/- vs. those infiltrating allografts in CCR5-/- recipients. The phenotype of allograft infiltrating myeloid cells was also altered in B6.CCR5-/-MPO-/- recipients and allograft histopathology on day 14 post-transplant indicated marked decreases in Mac-2+ activated macrophages in grafts from B6.CCR5-/-MPO-/- recipients. NanoString analysis of isolated myeloid cells infiltrating the kidney allografts of the two groups of recipients on day 14 post-transplant also indicated different transcriptomes, including decreased expression of gene pathways involved in phagocytosis, platelet degranulation, and endosomal TLR signaling by myeloid cells infiltrating allografts in B6.CCR5-/-MPO-/- recipients, that correlated with the histopathological change from acute to chronic ABMR. Overall, the results indicate that expression of MPO is required for activation of kidney allograft-infiltrating NK cells and monocytes/macrophages that promote acute AMR of kidney allografts and in the absence of recipient cells producing MPO DSA promotes development of chronic ABMR.