Background:Hepatocellular carcinoma (HCC) is a highly lethal liver cancer with late diagnosis; therefore, the identification of new early biomarkers could help reduce mortality. Efferocytosis, a process in which one cell engulfs another cell, including macrophages, dendritic cells, NK cells, etc., plays a complex role in tumorigenesis, sometimes promoting and sometimes inhibiting tumor development. However, the role of efferocytosis-related genes (ERGs) in HCC progression has been poorly studied, and their regulatory effects in HCC immunotherapy and drug targeting have not been reported.Methods:We downloaded efferocytosis-related genes from the Genecards database and screened for ERGs that showed significant expression changes between HCC and normal tissues and were associated with HCC prognosis. Machine learning algorithms were used to study prognostic gene features. CIBERSORT and pRRophetic R packages were used to evaluate the immune environment of HCC subtypes and predict treatment response. CCK-8 experiments conducted on HCC cells were used to assess the reliability of drug sensitivity prediction.Results:We constructed a prognostic prediction model composed of six genes, and the ROC curve showed good predictive accuracy of the risk model. In addition, two ERG-related subgroups in HCC showed significant differences in tumor immune landscape, immune response, and prognostic stratification. The CCK-8 experiment conducted on HCC cells confirmed the reliability of drug sensitivity prediction.Conclusion:Our study emphasizes the importance of efferocytosis in HCC progression. The risk model based on efferocytosis-related genes developed in our study provides a novel precision medicine approach for HCC patients, allowing clinicians to customize treatment plans based on unique patient characteristics. The results of our investigation carry noteworthy implications for the development of individualized treatment approaches involving immunotherapy and chemotherapy, thereby potentially facilitating the realization of personalized and more efficacious therapeutic interventions for HCC.