The main findings of the present study are as follows: (1) the ectopically expressed ISG15 increases overall protein ubiquitination, upregulates p53 and p21 expression, and ultimately enhances HCC cell apoptosis; (2) ISG15 either induced by IFN-α or transiently overexpression localizes in both nucleus and cytoplasm; and (3) overexpression of ISG15 could be developed into an efficient therapeutic strategy for IFN-α-resistant HCC and other cancers. This evidence concerns the gene ISG15 and cancer.