Background and Aims Liver cancer is one of the malignant tumors of the digestive system, characterized by high incidence and mortality rates. Cuproptosis, a novel copper-dependent form of cell death, occurs as a result of mitochondrial dysfunction induced by copper overload. Cuproptosis plays a significant role in various tumors, but its relationship with liver cancer remains unclear. Therefore, this study was conducted to investigate the expression characteristics of cuproptosis-related genes in liver cancer and their association with prognosis and immune infiltration.Methods Transcriptome data of liver cancer and normal liver tissues were downloaded from TCGA and GTEx databases for differential expression and mutation analysis. The R language "clusterProfiler" package was used for GO and KEGG enrichment analysis. LASSO, univariate, and multivariate regression analyses were employed to screen genes affecting the prognosis of liver cancer patients and a risk factor graph was constructed. A nomogram was constructed using the "rms" package in R. The UALCAN database was used to analyze the relationship between cuproptosis-related genes and clinicopathologic features of liver cancer and then the findings were validated. Spearman correlation analysis was used to examine the correlation between cuproptosis-related genes and immune cell infiltration and immune checkpoint expressions. TIMER2.0 database was used to analyze the correlation between the expressions of copper cuproptosis-related genes and cancer-associated fibroblast (CAF) infiltration, while TISDB database was utilized to analyze the correlation between CDKN2A and DLAT expression and myeloid-derived suppressor cell (MDSC) infiltration abundance.Results Compared to normal liver tissue, nine cuproptosis-related genes showed significantly increased expression in liver cancer, with CDKN2A having the highest mutation frequency. These genes were mainly involved in processes such as protein lipidation, tricarboxylic acid cycle, and citric acid cycle. Based on LASSO, univariate, and multivariate regression analysis, CDKN2A and DLAT were identified as genes influencing the overall survival (OS) of liver cancer patients, and a risk factor graph was constructed. Time-dependent ROC curves indicated their good predictive ability. Univariate and multivariate regression analysis revealed that CDKN2A, DLAT, T stage, and tumor status were independent prognostic factors for OS in liver cancer patients. A nomogram was constructed based on these factors, and calibration curves demonstrated good consistency between the predicted and observed values. UALCAN database analysis found associations of CDKN2A and DLAT with clinical stage and tumor grade in liver cancer, with validation results from GEO and HPA database as well as liver cancer cells aligning with these findings. Correlation analysis indicated that the expressions of CDKN2A and DLAT were correlated with immune cell infiltration and immune checkpoint expressions. TIMER2.0 database analysis revealed a significant positive correlation between DLAT expression and CAF infiltration, while TISDB database analysis showed no correlation of CDKN2A and DLAT expression with MDSC infiltration abundance.Conclusion Cuproptosis-related genes CDKN2A and DLAT may serve as novel prognostic biomarkers and potential targets for immunotherapy in liver cancer.