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Curcumin shows protective effects on various diseases due to its anti-inflammatory and anti-oxidative functions; however, its effect on organ transplantation has not been fully elucidated. To understand its role in liver ischemia/reperfusion (I/R) injury, we studied its impact on orthotopic liver transplantation (OLT) and Kupffer cells (KCs) polarization and its underlying mechanisms. We first investigated the reactive oxygen species (ROS) accumulation and cytokines profile of KCs, intracellular ROS and the mRNA level of pro-inflammatory cytokines were downregulated while the mRNA level of anti-inflammatory cytokine was upregulated by the pretreatment of Curcumin; Then the liver injury was detected by histopathological examination and liver function. Pretreatment with Curcumin significantly alleviated liver injury while improving liver function and overall post-transplantation survival compared with the control groups. The Western blotting showed that Curcumin inhibited the function of KCs via down-regulating the nuclear factor κb (NF-κb) signaling pathway by activating peroxisome proliferator-activated receptor γ (PPARγ) and flow cytometry revealed that Curcumin suppressed pro-inflammatory phenotype (M1) of KCs while promoting its anti-inflammatory phenotype (M2) polarization. These results showed that Curcumin may exert positive effects on I/R injury after OLT through activating PPARγ by inhibiting the activation of NF-κb pathway and remodeling the polarization of KCs. This may reveal a potential therapy for I/R injury after liver transplantation.Curcumin decreases the levels of ROS in KCs.Curcumin promotes KCs to anti-inflammatory polarization via activating PPARγ.Curcumin protects mice from OLT induced I/R injury through reshaping KCs’ polarization from M1 to M2.