Metastasis and recurrence are the biggest obstacles to enhance the efficacy of surgical resection as a cure for hepatocellular carcinoma which is the second most deadly cancer in China. Here, we had showed that two DNAzymes (DRz1 and DRz2) targeted to IGF-II could inhibit invasion, motility and migration of SMMC-7721 cells in vitro. DRz1 was transfected into SMMC-7721 cells and the results were shown that IGF-II expression level dramatically reduced. Meanwhile, DRz1 effectively inhibited adhesion between SMMC-7721 cells with the extracellular matrix and Fb cells comparing to those untreated or transfected with inactive DRz (P < 0.05, ANOVA). Furthermore, vascular endothelial growth factor and matrix metalloproteinases were down-regulated in DRz1 treated cells. These results may help to identify novel therapeutic molecules targeting hepatocellular carcinomas.