Renal ischemia-reperfusion injury (IRI) is a major risk factor for delayed graft function in renal transplantation. Compelling evidence exists that the stress-responsive enzyme, heme oxygenase-1 (HO-1) mediates protection against IRI. However, the role of myeloid HO-1 during IRI remains poorly characterized. Mice with myeloid-restricted deletion of HO-1 (HO-1 M-KO), littermate (LT), and wild-type (WT) mice were subjected to renal IRI or sham procedures and sacrificed after 24 hours or 7 days. In comparison to LT, HO-1 M-KO exhibited significant renal histological damage, pro-inflammatory responses and oxidative stress 24 hours after reperfusion. HO-1 M-KO mice also displayed impaired tubular repair and increased renal fibrosis 7 days after IRI. In WT mice, HO-1 induction with hemin specifically upregulated HO-1 within the CD11b + F4/80 lo subset of the renal myeloid cells. Prior administration of hemin to renal IRI was associated with significant increase of the renal HO-1 + CD11b + F4/80 lo myeloid cells in comparison to control mice. In contrast, this hemin-mediated protection was abolished in HO-1 M-KO mice. In conclusion, myeloid HO-1 appears as a critical protective pathway against renal IRI and could be an interesting therapeutic target in renal transplantation. Ischemia-reperfusion injury (IRI) is inherent to renal transplantation and leads to delayed graft function (DGF) of transplanted kidneys from deceased donors in up to 20 to 50% of cases 1, 2. Later, DGF contributes to the reduced longevity of the kidney allografts, notably because of a higher risk of acute and chronic rejection 3, 4. Basically, IRI is a two-phase phenomenon, including ischemia in the donor and reperfusion injury in the recipient. It combines major ischemia-induced cell stress, significant burst of free radicals, and intense inflammatory immune responses that lead to extensive cell injury, necrosis, and late interstitial fibrosis of the kidney allograft 1, 5. Today, the increasing demand for renal allografts implies more frequent use of organs issued from extended criteria donors and this change leads to an increased risk of DGF 6, 7. So far, there is no specific treatment of IRI and a better understanding of underlying mechanisms might lead to a better prevention of DGF and successful transplantations even with transplant from extended criteria donors. Several natural cellular mechanisms can confer resistance against IRI, including the ubiquitous heme oxy-genase (HO) cytoprotective pathway 8. Upon cellular stress, the expression of HO isoform 1 (HO-1, encoded by Hmox1) is significantly induced. The main action of HO-1 is the enzymatic degradation of free heme, a source of reactive species massively released during IRI. HO-1 metabolizes free heme into carbon monoxide, biliverdin that can both provide resistance against IRI 8. Interestingly, HO-1-deficient mice exhibit severe acute kidney injury (AKI) and death upon renal IRI 9, 10. In humans, reduced capacity of the donor to express HO-1 was associated