Histone acetylation is one of the most common epigenetic modifications and plays a crucial role in tumorigenesis. However, the prognostic significance of histone acetylation-related lncRNAs (HARlncRNAs) in esophageal carcinoma (ESCA) is not well understood. A total of 653 differentially expressed lncRNAs (DElncRNAs) were identified between 162 ESCA tissues and 11 normal tissues in the TCGA database, and 7 of them were correlated with acetylation regulators. We employed univariate Cox regression analysis, combining it with clinical prognosis information, to select 3 prognostic-related HARlncRNAs for further analysis. Subsequently, we used LASSO regression analysis to construct a risk signature for ESCA and identified
C21orf62-AS1
and
SSTR5.AS1
as potential biomarkers for the prognosis of ESCA patients. Based on the risk score calculated using the risk signature, we categorized patients into high- and low-risk groups. We identified the risk score as an independent risk factor and validated it in the training, test, and GSE53624 datasets. Additionally, patients categorized by their risk scores exhibited distinct immune statuses, tumor mutation burdens, responses to immunotherapy, and drug sensitivities.