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Background Human endogenous retroviruses (HERVs) harbor accessory proteins that influence cellular processes and have been linked to a wide variety of diseases, including cancer. This study investigates locus-specific HERV expression and its association with gene dysregulation in hepatocellular carcinoma (HCC), a highly prevalent and deadly form of liver cancer worldwide. Methods We analyzed RNASeq data from 424 HCC samples from The Cancer Genome Atlas (TCGA), which comprised 371 tumor and 50 matched normal tissues from a total of 371 hepatocellular carcinoma participants. We employed Telescope to identify and quantify HERV expression across the total RNA sequencing data. Results The majority of differentially expressed HERVs exhibited reduced expression in tumor tissue (166 downregulated vs. 50 upregulated), suggesting a potential functional role of HERV expression patterns in shaping the pathophysiological landscape of HCC. Specifically, the suppression of HERV-H family members, which are known to regulate cellular differentiation, may contribute to tumor dedifferentiation, increased plasticity, and enhanced metastatic potential. This loss of differentiation control and increased adaptability may play a critical role in driving the progression of liver cancer. Discussion Our study highlights a significant association of HERV expression with HCC, highlighting the differential regulation of specific HERV families in tumor tissue. For example, HERVH and ERVLE families showed consistent downregulation in tumor samples, while HERVE and HERV9 were more commonly upregulated. These shifts may reflect underlying changes in transcriptional regulation or chromatin structure between normal and malignant tissues. Rather than indicating a singular functional role, the observed expression patterns likely reflect a multifaceted relationship between HERVs and tumor biology. Further studies will be needed to determine whether these expression differences contribute to, or result from, tumor progression and to explore their potential as biomarkers or therapeutic targets.