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Background  Nonsynonymous tumor mutation burden (NSTMB) could affect the prognosis of esophageal cancer (EC) patients, but differentially expressed genes between EC patients with different NSTMB have not been explored. Our study aimed to compare differentially expressed genes between EC patients with different NSTMB (high vs. low).    Methods  RNA‐seq data for EC patients were downloaded from The Cancer Genome Atlas (TCGA). The edgeR package was used to identify differentially expressed genes between patients with different NSTMB. Cell type identification by estimating relative subsets of known RNA transcripts (CIBERSORT) software was employed to underscore immune cell differences between patients with different NSTMB.    Results  In total, we discovered 2215 differentially expressed genes between patients with different NSTMB, among which 842 genes were upregulated and 1373 downregulated in patients with high NSTMB. The differentially expressed genes were enriched in pathways such as heme binding and structural molecule activity. We built a logistic model that may be used to predict patients' NSTMB. We found that tumors with high NSTMB had a significantly higher percentage of resting natural killer (NK) cells than those with low NSTMB ( P  = 0.028). The percentages of regulatory T (Treg) and CD8 +  T cells were also higher in those with high NSTMB, although it was not statistically significant ( P  = 0.064 for Treg cells and  P  = 0.12 for CD8 +  T cells).    Conclusions  NSTMB may cause changes in gene expression and immune cell infiltration in EC patients, and affect the overall survival of EC patients.    Key points   Significant findings of the study   This study found differentially expressed genes and differences in infiltration of immune cells between esophageal cancer (EC) with different NSTMB.What this study adds   This study highlights differences between EC patients with different NSTMB.

Characterization of gene expression profiles of esophageal cancer patients with different nonsynonymous tumor mutation burden