HLA-G is a class I HLA that has gained much attention due to its multiple functions in the immune system. More important, some studies found HLA-G may be detrimental in tumors and viral infections, and the detection of HLA-G expression might serve as a clinical marker in the prediction of clinical outcomes for certain types of carcinoma. We assessed the association between the development of Kazakh esophageal squamous cell carcinoma (ESCC) harboring high-risk HPV infection and the expression of HLA-G. The expression of HLA-G was detected by S-P immunohistochemical staining in 60 cases of Kazakh ESCC tissues and 40 cases of Kazakh tumor adjacent normal tissues. HPV16 infection in ESCC was detected by genotype-specific polymerase chain reaction. HPV16 infection rate in Kazakh ESCC was 35.0%, significantly higher than that of the infection rate of the adjacent normal tissues 15% (p<0.05, OR=3.051; 95% CI: 1.103-8.438). The expression of HLA-G in Kazakh ESCC was 75.0% (45/60), significantly higher than that of tumor adjacent normal tissues (17.5%; p<0.05); expression of HLA-G was slightly higher in HPV16-positive than HPV16-negative ESCC, but the difference was not statistically significant (p>0.05). The positive expression rate of HLA-G was closely related to depth of invasion and clinical stage (p<0.05 for all), but was not related to age, sex, tumor location, histologic grade, and nodal status (p>0.05 for all). Overexpression of HLA-G was a characteristic feature of Kazakh ESCC; HLA-G may be involved in Kazakh ESCC carcinogenesis and HPV infection.