Objective To screen novel drugs for hepatocellular carcinoma (HCC) prevention based on drug repositioning strategy. Methods We collected the gene expression profiles of tissue samples representing the stepwise carcinogenic process covering 4 stages:cirrhosis, low-grade dysplastic nodule (LGDN), high-grade dysplastic nodule (HGDN) and early HCC, and identified the gene signatures between two consecutive stages. We also collected the gene expression data of human hepatocellular carcinoma cell lines HepG2 treated by 3 927 drugs and small molecules. The similarity between disease expressions and the drug gene expressions was calculated using gene set enrichment analysis (GSEA) algorithm, and drugs negatively correlated with the disease signatures were selected. Finally, we constructed the activated sub-network and performed pathway enrichment analysis to explore the underlying mechanisms of these drugs. Results We screened out the drugs that could prevent HCC during different stages, and found that importazole, picotamide and paclitaxel exhibited preventive potentials at all stages from cirrhosis to early HCC. The genes affected by these 3 drugs showed inverse expression pattern during HCC development, and pathways such as cancer-related pathway, p53 signaling pathway, focal adhesion and retinol metabolism pathway were enriched. Conclusion Preventive drugs for HCC have been screened through drug repositioning strategy, and our results indicated that antiplatelet therapy may play a role in the prevention of HCC, which provides information for further study.