Some functional polymorphisms in immune-regulating genes could affect the development of esophageal squamous cell carcinoma (ESCC). We enrolled 721 patients with ESCC and 1,208 healthy controls to explore the roles of rs2227282 (C > G) and rs2243283 (C > G) loci in the interleukin-4 (IL4) gene and rs1801275 loci in the interleukin-4 receptor (IL4R) gene for the occurrence of ESCC. As for IL4, the single nucleotide polymorphism rs2227282 (C > G) conferred an overall decreased risk for ESCC (adjusted P = 0.005, power = 0.816 in GG vs. CC genetic models). A stratification analysis of IL4 rs2227282 (C > G) and rs2243283 (C > G) and IL4R rs1801275 (A > G) loci with the ESCC risk revealed that the IL4 rs2243283 (C > G) polymorphism was a protective factor for the susceptibility to ESCC in some subgroups (women: power = 0.932 in CG vs. CC and 0.956 in CG/GG vs. CC; subjects aged ≥63 years: power = 0.844 in CG/GG vs. CC; never-smokers: power = 0.893 in CG vs. CC and 0.882 in CG/GG vs. CC; never-drinkers: power = 0.904 in CG vs. CC and 0.862 in CG/GG vs. CC). We also investigated the association of IL4 rs2227282 and rs2243283 and IL4R rs1801275 loci with the lymph node status. However, a null relationship was found. In conclusion, the present study highlighted that IL4 rs2227282 (C > G) and rs2243283 (C > G) loci are protective factors for the occurrence of ESCC.