Transcriptional dysregulation caused by genomic and epigenetic alterations in cancer is called “transcriptional addiction”. Transcriptional addiction is an important pathogenic factor of tumor malignancy. Hepatocellular carcinoma (HCC) genomes are highly heterogeneous, with many dysregulated genes. Our study analyzed the possibility that transcriptional addiction-related genes play a significant role in HCC. All data sources for conducting this study were public cancer databases and tissue microarrays. We identified 38 transcriptional addiction genes, and most were differentially expressed genes. Among patients of different groups, there were significant differences in overall survival rates. Both nomogram and risk score were independent predictors of HCC outcomes. Transcriptional addiction gene expression characteristics determine the sensitivity of patients to immunotherapy, cisplatin, and sorafenib. Besides, HDAC2 was identified as an oncogene, and its expression was correlated with patient survival time. Our study conclusively demonstrated that transcriptional addiction is crucial in HCC. We provided biomarkers for predicting the prognosis of HCC patients, which can more precisely guide the patient’s treatment.