Abstract: OBJECTIVE To observe the relationship between single nucleotide polymorphisms (SNPs) of P53 gene, human papillomavirus (HPV)16/18 infections and esophageal cancer. METHODS Totally 103 patients with esophageal cancer ( the esophageal cancer group) and 100 patients with esophageal mucositis lesions (the control group) who were treated in the People's Hospital of Chongqing Liangjiang New Area from May 2018 to May 2021 were enrolled in the study. The SNPs of P53 gene were detected by means of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and the HPV16/18 subtypes were detected by PCR. RESULTS There were significant differences in the frequencies of Pro/Pro, Pro/Arg, Arg/Arg genotypes and Pro, Arg alleles at rs1042522 locus of P53 gene between the two groups (P＜0.05).The polymorphisms at rs1042522 locus of P53 gene were associated with the degree of differentiation, TNM stage and lymph node metastasis(P＜0.05). The positive rate of HPV16 of the esophageal cancer group was 52.43%, higher than 16.00% of the control group; the positive rate of HPV18 of the esophageal cancer group was 32.04%, higher than 10.00% of the control group(P＜0.05). Among the esophageal cancer patients, the proportions of the HPV16- and HPV18-psitive patients who carried with Arg/Arg genotype at rs1042522 locus of P53 gene were higher than those of the HPV16- and HPV18-negative patients (P＜0.05). CONCLUSION The polymorphism at rs1042522 locus of P53 gene may be one of the factors for genetic susceptibility of esophageal cancer, and the patients who carry with Arg/Arg genotype are more likely to have HPV16/HPV18-related esophageal cancer.