After NDV infects the liver tumour cell，USP18 （Ubiquitin Specific Protease 18） acts as a deubiquitin enzyme and cleaves ubiquitin from ubiquitinated protein substrates. NDV infection of liver tumour cell can induce the apoptosis of cancer cells. Infection with NDV up-regulates the expression of USP18，and the role of USP18 in the apoptosis induced by NDV was investigated. In this study, the liver tumour cell line Huh7 is taken as the system, and western blot and qualitative PCR are considered. It is found that USP18 promotes the apoptosis of cancer cells induced by NDV，which demonstrates that USP18 has the anticancer function. In contrast, knock-down of USP18 inhibits the apoptosis of the cancer cells, which reveals that USP18 can positively regulate the protein level of Bax and NOXA. Consistently，overexpression of USP18 enhances the permeability of mitochondrial membrane and promotes the release of CYTOCHROME C. Similarly, overexpression of USP18 increases the cleaved caspase-7 and strengthens the apoptosis as well. It is also found that USP18 can upregulate the protein level of ISG12a（IFN-stimulated gene 12a）. It attenuates the ubiquitination degradation of ISG12a. The findings in this research provide a profound influence and a new insight towards treatment for liver cancer.