Background the roles of RNA-binding proteins (RBPs) in esophageal cancer (EC) need elucidation. Materials and methods The gene expression profiles and clinical data of patients with EC were downloaded from the Xena database. Candidate genes were obtained by taking the union of RBP genes, KEGG pathway-related genes and differentially expressed RBP genes from cluster analysis. Hub genes were extracted by PPI network construction. Result We built a Cox proportional hazards regression model with 7

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... rognostic RBPs (TRMT2A, PDHA1, MPRIP, KRI1, IL17A, HSPA1A and HIST1H4J). The risk score of each patient in the internal and external dataset cohorts was calculated and then the patients were divided into two groups based on the median. There were significant differences between the RBP risk score and response to chemotherapy, with low-risk patients being more likely to achieve CR. Finally, the risk score was revealed to be significantly related to OS by univariate and multivariate analyses, and pathological stage could also be used independently to predict the prognosis of EC. Conclusion Our study indicated that the RBP signature could serve as a prognostic biomarker of EC and provide new insight into chemoresistance in EC patients.