Our aim was to investigate whether polymorphisms in the interleukin-4 (IL-4) gene are associated with the risk of colorectal cancer (CRC) in a Chinese Han population. Six single-nucleotide polymorphisms (SNPs) in the IL-4 were genotyped by Agena MassARRAY in 248 CRC patients and 463 healthy controls. The association of IL-4 polymorphisms with CRC risk was assessed by genetic models, linkage disequilibrium, and haplotype analyses. The results suggested that the CC genotype of rs2243250 confers a lower risk of CRC in the recessive model [odds ratio (OR) = 0.42, 95% confidence interval (CI): 0.19-0.92, P = 0.020]. Similarly, rs2227284 GG was associated with a reduced risk of CRC in the codominant (OR = 0.18, 95% CI: 0.04-0.82, P = 0.027) and recessive (OR = 0.19, 95% CI: 0.04-0.83, P = 0.008) models adjusted for age. Our findings suggested that rs2243250 and rs2227284 in IL-4 are associated significantly with reduced CRC risk, which may facilitate the identification of CRC patients in Chinese populations.