Based on transcriptomic data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), as well as in vivo and ex vivo experiments, this study investigated the expression of SETDB1 and its influence on the malignant biological behavior of HCC, as well as its correlation with the clinical characteristics, prognosis, and immune cell infiltration. The gene discussed is SETDB1; the disease is hepatocellular carcinoma.