AbstractInflammation and ferroptosis crosstalk complexly with immune microenvironment of hepatocellular carcinoma (HCC), thus affecting the efficacy of immunotherapy. Herein, our aim was to identify the inflammation‐associated ferroptosis (IAF) biomarkers for contributing HCC. A total of 224 intersecting DEGs identified from different inflammation‐ and ferroptosis‐subtypes were set as IAF genes. Seven of them includingADH4,APOA5,CFHR3,CXCL8,FTCD,G6PDandPON1were used for construction of a risk model which classified HCC patients into two groups (high and low risk). HCC patients in the high‐risk group exhibited shorter survival rate and higher immune score, and were predicted to have higher respond rate in immune checkpoint inhibition (ICI) therapy. Levels of the seven genes were significantly changed in HCC tissues in comparison to adjacent tissues. After inserting the gene expression into the risk model, we found that the risk model exhibited the higher diagnostic value for distinguish HCC tissues compared each single gene. Furthermore, HCC tissues from our research group with high‐risk score exhibited more cases of microsatellite instability (MSI), heavier tumour mutational burden (TMB), higher expression level of PDL1 and cells with CD8. Knockdown ofAPOA5reduced HCC cell proliferation combining with elevating inflammation and ferroptosis levels. In conclusion, we consideredAPOA5maybe a novel target for suppressing HCC via simultaneously elevating inflammation and ferroptosis levels, and signature constructed by seven IAF genes includingADH4,APOA5,CFHR3,CXCL8,FTCD,G6PDandPON1can act as a biomarker for optimising the diagnosis, prognosis evaluation and immunotherapy options in HCC patients.