The correlation between TBX21 gene (T-box transcription factor protein 21; T-bet), which was a pivotal transcriptional regulation gene for Th1/Th2 polarization, and the development risk of esophagus squamous cell carcinoma (ESCC) was assessed in a high-risk Chinese population. A total of 302 ESCC cases and 311 normal controls coming from the highest incidence area of China were enrolled in this study. Three polymorphisms at -1499, -1514, and -1993 located in the TBX21 promoter were identified by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Logistic regression was used to determine whether the inherited variations of the TBX21 gene would associate with the risk and the clinicopathological characteristics of ESCC. Among the ESCC patients, an association between the TBX21 -1514T/C or -1993T/C polymorphisms and the lymph node or distant metastasis was found (odds ratios (ORs) were 9.46 and 4.35, respectively, all P < 0.01). By the log-additive model analysis, the results exhibited that three haplotypes, ACC, ACT, and ATC, were significantly related to the development risk of ESCC (OR = 11.81, 3.44, 2.37, respectively, all P < 0.05). TBX21 gene -1514 and -1993 polymorphisms might be counted as the influential factors for lymph node and distant metastasis to ESCC. Especially, the ACC, ACT, and ATC haplotypes derived from the TBX21 gene would increase the susceptibility to ESCC in the high-risk Chinese population.