Objective To investigate the impact of recombinant human erythropoietin（rhEPO）pretreatment on liver ischemia-reperfusion injury（IRI）in rats and explore the molecular mechanism. Methods Thirty male Sprague-Dawley（SD）rats were randomly divided into three groups equally, including Sham，control and rhEPO groups. Rats in rhEPO group were treated with rhEPO（5 000 U/kg）1 hour before IR induction while sham and control groups were pretreated with saline. 70% liver IR rat model was established in control and rhEPO groups except for sham group. Rat liver tissues and serum were harvested for hematoxylin and eosin（HE）staining，Western Blot，qPCRand enzyme linked immunosorbent assay（ELISA）assay, respectively. Liver histology，transaminases（AST，ALT）， pro-inflammation cytokines（TNF-α，IL-6，IL-1β）and PI3K/AKT signaling were investigated. Results Distinct liver injury was observed with a higher histological damage score and the release of AST and ALT in serum after 70% tissue IR process. rhEPO significantly decreased the pathologic changes of liver and the release of AST and ALT in serum〔AST（U/L）：582.0±52.5 vs. 245.0±31.7 ；ALT（U/L）：388.0±39.6 vs. 166±24.3，both P ＜ 0.05〕. The expression of p-p85 and p-AKT were increased in rhEPO group compared to control group. TNF-α，IL-6 and IL-1β mRNA levels were demonstrated to ascend after IR but lower expression was observed in rhEPO group. Remarkable IRI-induced secretion of TNF-α，IL-6 and IL-1β proteins in serum was verified but rhEPO inhibited the secretion〔TNF-α（pg/ml）：425.0±31.2 vs. 227.0±19.7；IL-6（pg/ml）：353.0±26.4 vs. 189.0±16.3；IL-1β （pg/ml）：511.0±39.6 vs. 328.0±23.2 ，all P ＜ 0.05）〕. Conclusion rhEPO pretreatment can reduce the release of pro-inflammation cytokines and protect liver from IRI in rats through enhanced activation of PI3K/AKT signaling.