Abstract- Cilostazol is an antiplatelet that acts by inhibiting phosphodiesterase-3 and that was proven to be effective in models of ischemia/reperfusion (I/R) injury; however, its possible role in hepatic I/R remains indistinct, which is the aim of the current work. To fulfill this goal, rats were randomized into sham, I/R and cilostazol (60mg/kg, p.o) groups. The hepatic artery and portal vein to the left and median liver lobes were occluded for 30 min and then declamped for reperfusion to establish a model of segmental (70%) warm hepatic ischemia. Pretreatment of animals with cilostazol for two weeks prior to I/R insult significantly decreased serum alanine aminotransferase, and inhibited I/R-induced hepatocytes apoptotic death signified by inhibition of caspase-3. Moreover, cilostazol increased ATP content and lowered the level of lipid peroxidation assessed as malondialdehyde. The drug also elevated the nitric oxide content and decreased that of tumor necrosis factor-α, as well as the myeloperoxidase activity, a marker of neutrophil infiltration. Mechanistic studies revealed that cilostazol protected the liver and enhanced its proliferation ability, where it markedly increased the level of β-catenin and cyclin D1, but blocked the phosphorylation of GSK-3β at Ser9. In conclusion, cilostazol pre-administration protected hepatocytes against I/R insult by virtue of its antioxidant, anti-inflammatory, and antiapoptotic effects; besides, the drug increased hepatocytes proliferation by increasing the level of cyclin D1. It increased also the Wnt/ β-catenin pathway, which aid in its hepatoprotective action along with blocking the GSK-3β phosphorylation at the ser9, which had injurious role in this work.