It has been reported that chromatin regulators (CRs), as one of the essential upstream regulators of tumor development, were screened to construct a prognostic model for predicting the outcome of tumor patients. However, the prognostic model based on CRs-related long noncoding RNAs (lncRNAs) in esophageal cancer (EC) has never been researched. This study aims to construct a novel CRs-related lncRNA signature to evaluate the prognostic ability of EC patients. We obtained the transcriptome data and clinical information of patients with EC from the Cancer Genome Atlas database, 870 CRs-related genes from previous topic research. Univariate, multivariate Cox, the least absolute shrinkage and selection operator regression analyses were used to establish the risk model. The receiver operating characteristic curve, principal component analysis, nomogram, quantitative real-time PCR were performed to evaluate the independence and accuracy of the model. The biological functions and immune microenvironment of the risk model were analyzed by gene set enrichment analyses and R softwares. A novel 3 CRs-related lncRNAs risk model composed of AC079684.1, TMEM75, LINC00365, as an independent and superior factor, was established for prognosis prediction of EC patients. Quantitative real-time PCR analysis verified upregulated AC079684.1 and TMEM75 mRNA levels and downregulated LINC00365 mRNA level in EC tissues compared with normal tissues. Gene set enrichment analysis analysis displayed Kyoto encyclopedia of genes and genomes and gene ontology pathways enriched in risk groups, such as focal adhesion, pathways in cancer, epidermal cell differentiation. Immune cells and immune checkpoints were more likely to be activated in the high-risk group. Finally, we found most of the compounds in the high-risk group exhibited higher sensitivity through therapeutic drug screening. The 3 CRs-related lncRNAs risk model could independently predict the prognosis of EC and provide immunotherapy guidance for patients with EC.Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.