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Individual genetic background can play an essential role in determining the development of esophageal squamous cell carcinoma (ESCC).  PTPN13  and  CHEK2  play important roles in the pathogenesis of ESCC. This case-control study aimed to analyze the association between gene polymorphisms and ESCC susceptibility. DNA was extracted from the peripheral blood of patients. The Agena MassARRAY platform was used for the genotyping. Statistical analysis was conducted using the chi-squared test or Fisher’s exact test, logistic regression analysis, and stratification analysis. The ‘G’ allele of rs989902 ( PTPN13 ) and the ‘T’ allele of rs738722 ( CHEK2 ) were both associated with an increased risk of ESCC (rs989902: OR = 1.23, 95% CI = 1.02–1.47,  p  = 0.028; rs738722: OR = 1.28, 95% CI = 1.06–1.55,  p  = 0.011). Stratification analysis showed that SNPs (rs989902 and rs738722) were notably correlated with an increased risk of ESCC after stratification for age, sex, smoking, and drinking status. In addition, rs738722 might be associated with lower stage, while rs989902 had a lower risk of metastasis. Our findings display that  PTPN13  rs989902 and  CHEK2  rs738722 are associated with an increased risk of ESCC in the Chinese Han population.

PTPN13 rs989902 and CHEK2 rs738722 are associated with esophageal cancer