Background Hepatocellular carcinoma (HCC) is the seventh most commonly occurring cancer and the second most common cause of cancer-related death worldwide. Despite improvements in early detection and treatment, the morbidity and mortality remain high because of complex molecular mechanisms and cellular heterogeneity in HCC. However, novel model is still needed to predict the survival and clinical immunotherapy response in HCC.Methods 13 iron metabolism-related gene sets were identified from the GSEA. DEGs associated with iron metabolism were calculated between patients who survived Results Here we established a gene signature using iron metabolism-related genes form the Cancer Genome Atlas (TCGA), and the survival outcomes were validated from International Cancer Genome Consortium(ICGC). Distinct subtypes (high- and low-risk subtypes) were characterized by different clinical outcomes. The high-risk subtype was featured by better survival outcomes, upregulated cell cycle relevant pathways and better response for immunotherapy.Conclusions Our finding suggested that the novel model may be useful as a biomarker for prognostic predication, immunotherapy and cell cycle inhibitors may be efficacious for high-risk subtype of HCC patients.