Abstract: Hepatocellular carcinoma（HCC） is one of the most common malignant tumors worldwide with high morbidity, poor prognosis and mortality. DNA methylation plays an important role in HCC tumorigenesis and progression. In this study, HCC methylation data, RNA-seq data and clinical prognosis information were obtained from The Cancer Genome Atlas（TCGA） database. MethylMix R package was used to screen out the differential methylation status in cancer tissues and normal tissues, and 338 disease-related methylation-driven genes were obtained. DAVID and ConsensusPathDB were respectively used to analyze the functional and pathways enrichment of these genes. Then, a prognostic risk model based on 5 methylation-driven gene expression profiles was constructed by univariate and multivariate Cox regression analysis. At the same time, a methylation and gene expression combined survival analysis was performed to further explore the prognostic value of these 5 genes and their methylation sites. This study will provide new markers and new ideas for the early diagnosis and prognosis assessment of HCC.