OBJECTIVE: This study aims to integrate bulk and single-cell RNA sequencing data to construct a risk score model based on HOXC9-related immune genes (HRIGs) and evaluate its prognostic value in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: RNA sequencing data and clinical information of HCC were obtained from TCGA and GEO databases. HRIGs were identified and a risk score model was constructed using LASSO-Cox regression analysis. The association between the risk score and tumor microenvironment was analyzed using CIBERSORT and ESTIMATE algorithms. Single-cell RNA sequencing (scRNA-seq) data were used to assess cell type distribution. Cell experiments were conducted to verify the effects of HOXC9 knockdown on HCC cell proliferation and invasion. RESULTS: HOXC9 is highly expressed in HCC and associated with poor prognosis (p=0.031). The risk score model based on four HRIGs (EGLN3, IMPDH1, LPCAT1, and MARCKSL1) showed good prognostic discrimination in both TCGA and GEO cohorts, with significantly lower overall survival in the high-risk group (p<0.0001). The high-risk group exhibited higher immune scores and increased immune cell infiltration, as well as elevated immune checkpoint expression. scRNA-seq revealed increased hepatocytes and fibroblasts but decreased T/NK cells in HCC tissues. HOXC9 knockdown significantly inhibited HCC cell proliferation and invasion. CONCLUSION: HOXC9 is overexpressed in HCC and correlates with poor prognosis. The HRIG-based risk score model effectively evaluates the prognosis and immune response in HCC patients, providing new insights for risk assessment and immunotherapy prediction.