BACKGROUND: Hepatocellular carcinoma (HCC) represents one of the most prevalent malignant neoplasms worldwide, characterized by poor prognosis and low 5-year survival rates. Despite extensive research, its pathogenesis remains largely unclear. Within the tumor microenvironment (TME), monocytes play a dual role: they participate in tumor cell recognition and elimination while regulating immune responses through cytokine secretion. This study aims to investigate the association between differentially expressed genes in monocytes and HCC development. METHODS: This investigation employed single-cell transcriptomic analysis of human hepatic innate lymphoid cells (ILCs) to identify monocyte subpopulations and their cellular markers. Subsequently, two-sample Mendelian randomization (MR) analysis was conducted to examine the causal relationships between these cells, their associated genes, and HCC development. RESULTS: Through comprehensive analysis of the monocyte cluster, we identified 2338 differentially expressed genes (DEGs). MR analysis revealed 13 genes significantly associated with HCC risk: CONCLUSION: This study represents the first integration of single-cell sequencing technology with MR analysis to investigate the relationship between monocytes and HCC. Through this innovative methodological approach, we have revealed potential associations between monocyte gene expression and HCC development, providing new directions for further research on HCC prevention and treatment, as well as identifying potential therapeutic targets.