〔Abstract〕 Objective To explore the role and mechanism of plasmalemma vesicle-associated protein(PLVAP) in the progression of hepatocellular carcinoma(HCC). Methods Bioinformatic analysis, quantitative real-time PCR, Western blot and immunohistochemistry were used to analyze the expression level of PLVAP in HCC and paracancerous tissues, and its correlation with clinicopathological characteristics. Stable HCC cell lines with knockdown and overexpression of PLVAP were constructed, then cell proliferation, migration and invasion of HCC cells were examined by CCK-8, foci formation assays, wound-healing assays and Transwell assays. Western blot was used to detect the protein levels of phosphatidylinositol 3-kinase PI3K, phosphorylated phosphatidylinositol 3-kinase p-PI3K, protein kinase B AKT and phosphorylated protein kinase B p-AKT in the PI3K/AKT pathway after PLVAP knockdown and overexpression. Cell proliferation, migration and invasion were also examined in PLVAP-overexpressed cells after treatment of LY294002, an inhibitor of the PI3K/AKT pathway. Results The expression of PLVAP was significantly higher in HCC tissues than that in adjacent non-tumor tissues(P<0.05), and was positive correlated with tumor stage, T stage, M stage, and microvascular invasion(P<0.05). Knockdown of PLVAP significantly reduced the proliferation, migration and invasion of HCC cells(P<0.001), while overexpression of PLVAP significantly increased the proliferation, migration and invasion of HCC cells(P<0.01). Western blot analysis revealed that knockdown of PLVAP decreased the protein expression levels of p-PI3K and p-AKT, overexpression of PLVAP increased the protein expression levels of p-PI3K and p-AKT, whereas the PI3K/AKT inhibitor LY294002 eliminated the effects of PLVAP on cell proliferation, migration and invasion(P<0.01). Conclusion PLVAP is highly expressed in HCC and may promote HCC progression by activating the PI3K/AKT signaling pathway.