Objective To observe the expression of XB130 in human hepatocellular cells and the effect of XB130 down-regulating on proliferation and survival. Methods Expression of XB130 in human hepatocellular carcinoma cell-lines was detected by Western blot and (qRT)-PCR. Small interfere RNA (siRNA) was transfected into Hep3B cell to down-regulate XB130 expression and interfering effect, and proliferation and survival related gene was detected by Western blot and (qRT) -PCR. Proliferation, cell cycle and apoptosis were detected by MTT and flow cytometry. Results XB130 protein and RNA was expressed in Hep3B, Huh7, HepG2 and MHCC97H cells, highest in Hep3B cell (F = 5.742, P < 0.01; F = 3.452, P <0.05); Compared with siNC group, p-p21 and p-Akt protein in siXB130 group was lower (t = 8.462, P < 0.01; t = 9.742, P < 0.01), p21, Akt, Cleaved Capase-8 and Cleaved Capase-9 protein was higher (t = 12.247, P < 0.01; t = 6.452, P < 0.01; t = 11.634, P < 0.01; t = 12.273, P < 0.01); Compared with siNC group, at 72 h and 96 h, proliferation of Hep3B cells wad decreased (t = 8.176, P < 0.01; t = 2.246, P < 0.05), more Hep3B cells stayed at G1 phase, less stayed at G2 and S phase (t = 4.23, P <0.05; t = 2.13, P < 0.05; t = 5.72, P < 0.05), apoptosis rate was increased (t = 8.633, P < 0.01). Conclusions siXB130 down-regulating inhibits apoptosis and survival via p-21 phosphorylation and PI3K/Akt signal pathway in hepatocellular carcinoma cells and may be a target candidate for hepatocellular carcinoma therapy.