Background: Exertional rhabdomyolysis (ER)-induced acute kidney injury (AKI) is a serious health threat associated with strenuous physical exercise. Erythropoietin (EPO) is a pleiotropic hormone with its immunomodulator function still unclear. We investigated the renoprotective effect of EPO in EXR-induced AKI, with an emphasis on macrophages phenotypic polarization and associated hemeoxygenase1 (HO1) bioactivity. Methods: Strenuous exercise was applied torats, either or not preceded by EPO alone or combined with theHO1enzymeblocker,Zincprotoporphyrins(Zn-PP).Serum levelsofcreatinephosphokinase,myoglobin, urea nitrogen, creatinine, and carboxyhemoglobin (COHb) % were estimated. In addition, we examined the inflammatory cytokines IL10 and TNFα, macrophages phenotypic markers, HO1 expression, and renal pathology. Results: EPO pre-treatment resulted in significant decreases in blood urea nitrogen, serum creatinine and myoglobin, tubular injury score, and intratubular cast % in addition to TNF-α decrease, IL10 increase with a preferential switching of macrophage polarization to the reparative M2 phenotype as antiinflammatory effect. Furthermore, EPO pre-treatment was associated with an increase in HO1 protein expression and COHb%. Such effects were significantly reversed when HO1 activity blocker, Zn-PP, was co-administered. Am. J.Biomed.Sci.2018,10(4),223-236;doi:10.5099/aj180400223 © 2018byNWPII.All rightsreserved 224 Conclusion: Our findings highlight the value of EPO as a prophylactic therapeutic agent against EXRinduced AKI. Additionally, they suggest an underpinning role for HO1 in the EPO-induced modulation of macrophagepolarizationtowardstheM2phenotype