Multiple determinant factors are involved in the occurrence and progression of esophageal squamous cell carcinoma (ESCC). Human papillomavirus (HPV) and human leukocyte antigen (HLA) polymorphism were identified as important factors. This study examined the associations between the development of Kazakh ESCC and the determinant factors including HLA-DRB1*0901, 1501; DQB1*0301, 0602; high-risk HPV infection in the area of Xinjiang, China. 200 Kazakh patients with ESCC and 150 controls were recruited, and polymerase chain reaction (PCR) was performed to detect HLA-DRB1*0901, 1501 and DQB1*0301,0602 using sequence-specific primers (SSPs). HPV16 was detected in esophageal specimens using PCR. HPV16 infection rate in Kazakh ESCC case group was 41 %, significantly higher than that of control group 14 % (OR = 3.62; 95 % CI, 2.15-6.09; P < 0.001). A positive association between ESCC and HLA-DRB1*1501 (OR = 2.46, P < 0.0125) or HLA-DQB1*0301 (OR = 3.34, P < 0.0125) alleles was observed. Similar tendencies were observed for HLA-DRB1*1501 (OR = 3.095, P < 0.0125) and HLA-DQB1*0301 (OR = 2.410, P < 0.0125) alleles with HPV16-positive ESCC. HLA-DRB1*1501, HLA-DQB1*0301 and DQB1*0602 were significantly associated with ESCC when the age was ≥55 years (P < 0.0125 for all), whereas only HLA-DQB1*0301 was significantly associated with ESCC when the age was <55 years (P < 0.0125). HLA-DRB1*1501 and HLA-DQB1*0301 were significantly associated with an increase in ESCC occurrence in females (P < 0.0125), whereas only HLA-DQB1*0301 was significantly associated with ESCC in males. Moreover, the occurrence of HLA-DQB1*0602 gene in poorly differentiated ESCC group (68.8 %) was slightly higher than that of well-differentiated squamous cell carcinoma group (31.2 %). The difference was not statistically significant (P > 0.0125). The study suggests that HLA-DRB1*1501 and HLA-DQB1*0301 may influence the immune response to specific tumor and HPV-encoded epitopes and affect the risk of Kazakh ESCC in XinJiang, China.