EPCs play an important role in tumor growth and metastasis. Therefore, it is worthwhile to study whether FTY720 suppresses liver tumor metastasis after surgical resection by attenuating hepatic I/R injury and reducing circulating EPCs. In the present study, the effect of FTY720 on inhibition of liver tumor metastasis after liver resection and I/R injury was first shown in an orthotopic rat liver tumor model with local and distant metastatic potentials. This model effectively mimicked clinical liver tumor metastasis situation after liver surgery. In addition to reduce the incidence of tumor metastasis, FTY720 also significantly decreased the number and size of metastatic tumor nodules at four weeks after liver resection and hepatic I/R injury. In this study, our Naringin dihydrochalcone results showed that FTY720 significantly reduced the number of circulating and bone marrow EPCs. The phenomenon was consistent with the decrease of MVD in metastatic tumor nodules. EPCs play important roles in tumor vasculogenesis and tumor growth at early phase. Our results also confirmed that in both treatment and control groups, the level of circulating EPCs was higher in the rats with metastasis than without metastasis. Clinafloxacin several studies in mice and human have demonstrated that EPCs derived from bone marrow contribute to tumor angiogenesis. The extent of the contribution depended on the tumor type, host and stage of tumorigenesis. EPCs ablation can result in significant angiogenesis inhibition and impaired tumor growth and metastasis. Furthermore, EPCs have major roles in tumor progression from micrometastases to macrometastases. Therefore, the effect of FTY720 on inhibition of liver tumor metastasis was probably due to the decrease of circulating EPCs level. Targeting circulating EPCs by FTY720 treatment may effectively decrease tumor metastasis and block metastasis progression from micrometastases to macrometastases. However, the direct effects of FTY720 on the generation of EPCs in bone marrow need to be further investigated. To investigate the underlying mechanism of FTY720 on suppression of circulating EPCs, the expression level of several inflammatory chemokines and cytokines were analyzed. Our studies indicated that FTY720 significantly attenuated hepatic I/R injury and down-regulated intracellular mRNA and protein levels of CXCL10, VEGF, CXCR4 and CXCR3. Several researches show that surgery stress injury such as I/R injury during liver resection and liver transplantation rapidly enhances the number of circulating EPCs. Mobilization and migration of EPCs is also associated with elevated levels of angiogenic growth factors or chemokines. Recent studies demonstrate that VEGF, CXCR3 and CXCR4 could play important roles in the migration of circulating EPCs and enhanced vasculogenesis which subsequently contribute to neovascularization. Vascular endothelial growth inhibitor effectively inhibits mobilization and differentiation