Background: Esophageal squamous cell carcinoma (ESCC) is a malignant tumor with a strong tendency toward familial aggregation and a higher incidence as well as mortality in Kazakh population. Tumor necrosis factor-alpha (TNF-alpha) is an important inflammatory cytokine that plays a role in controlling the progression of lung cancer, hepatocellular cancer, breast cancer and gastric cancer. But the association between TNF-alpha-308G/A and ESCC still remains unclarified. Materials and Methods: Here, we investigated the potential associations between the TNFa- 308G/A and susceptibility to ESCC in 212 cases and 200 controls from a pure ethnic population of Kazakh. DNA extraction and Real-time PCR were performed to detect the TNF-alpha-308G/A expression levels and odd ratios (ORs) with the corresponding 95% confidence interval (CI) were to evaluate their association with TNF-alpha-308G/A polymorphism. Results: We found that the frequencies of TNF-alpha-308G/A in the cases were similar to that of the controls with no differences being statistically significant (chi(2)=1.23, P>0.05). Using the G allele as the reference genotype, individuals who carried A allele had a significantly increased risk of developing ESCC (OR=2.64, 95% CI=1.31 similar to 5.35). Especially, the G/A+A/A genotype are associated with increased risk of metastatic as compared with GG genotype individuals (OR=2.08, 95% CI=1.14-3.80, P=0.02). Conclusions: Our findings suggest that though the TNF-alpha-308G/A polymorphism may not be correlated with the susceptibility to Kazakh's ESCC in Xinjiang, patients who carry A allele tend to poorly differentiated and lymph node metastasis.