Objective：This study aims to investigate the role of HOXA5 in HCC progression. Methods：RT-qPCR，Western blot，IHC were carried out to detect the expression of HOXA5 in HCC tissues and adjacent peritumor tissues. Hep3B and MHCC97H cells were chosen to establish the knockdown model. Colony formation assay，EdU assay，and CCK8 assay were performed to demonstrate the proliferation ability of HCC cells. Transwell assay and FACS technology were used to detected invasion and anti-apoptosis ability of HCC cells separately. Finally，Western blot was carried out to further confirm the possibile role that HOXA5 played in PI3K-AKT signal pathway. Results：Expression of HOXA5 at mRNA and protein level in HCC tissues were significantly higher than that in adjacent peritumor tissues. Knockdown of HOXA5 could reduce the proliferation，invasion and anti-apoptosis ability of HCC cells. Knockdown of HOXA5 could decrease the expression of phosphorylated PI3K and phosphorylated AKT，while ectopic expression of HOXA5 promoted the activation of this pathway. Conclusion：The expression of HOXA5 in HCC tissues is higher than that in adjacent tissues. Manipulation of HOXA5 expression in HCC cells had an impact on their proliferation，anti-apoptosis ability，invasion ability and activation of the PI3K-AKT signaling pathway in vitro.