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Background: Oxidative stress plays a critical role in oncogenesis and tumor progression. However, the prognostic role of oxidative stress-related lncRNA in hepatocellular carcinomas (HCC) has not been fully explored.Methods: We used the gene expression data and clinical data from The Cancer Genome Atlas (TCGA) database to identify oxidative stress-related differentially expressed lncRNAs (DElncRNAs) by pearson correlation analysis. A four-oxidative stress-related DElncRNA signature was constructed by LASSO regression and Cox regression analyses. The predictive signature was further validated by Kaplan–Meier (K–M) survival analysis, receiver operating characteristic (ROC) curves, nomogram and calibration plots, and principal component analysis (PCA). Single-sample gene set enrichment analysis (ssGSEA) was used to explore the relationship between the signature and immune status. Finally, the correlation between the signature and chemotherapeutic response of HCC patients was analyzed.Results: In our study, the four-DElncRNA signature was not only proved to be a robust independent prognostic factor for overall survival (OS) prediction, but also played a crucial role in the regulation of progression and chemotherapeutic response of HCC. ssGSEA showed that the signature was correlated with the infiltration level of immune cells. HCC patients in high-risk group were more sensitive to the conventional chemotherapeutic drugs including Sorafenib, lapatinib, Nilotinib, Gefitinib, Erlotinib and Dasatinib, which pave the way for targeting DElncRNA-associated treatments for HCC patients.Conclusion: Our study has originated a prognostic signature for HCC based on oxidative stress-related DElncRNAs, deepened the understanding of the biological role of four key DElncRNAs in HCC and laid a theoretical foundation for the choice of chemotherapy.