Introduction: Interleukin-22 (IL-22), an IL-10 family cytokine produced by T cells and innate lymphoid cells, is implicated in inflammation and tumorigenesis. In this study, we aimed to investigate the association of IL-22 polymorphisms with the colon cancer in a Chinese population. Materials and methods: Five hundred forty colon cancer cases and 540 healthy controls were recruited in the case-control study. The fluorogenic 5' exonuclease assays were used for genotype analysis of three common polymorphisms (-429C/T, + 1046 T/A and +1995 A/C) of the IL-22 gene. Results: Colon cancer cases had a significantly higher frequency of IL-22-429 TT genotype [odds ratio (OR) = 1.69, 95% confidence interval (CI) = 1.24, 2.30; P = 0.001] and -429 T allele (OR = 1.35, 95% CI = 1.14, 1.60; P = 0.001) than healthy controls. The findings are still emphatic by the Bonferroni correction (P < 0.017). When stratifying by the differentiation of colon cancer, we found that colon cancer cases with poor differentiation had a significantly higher frequency of IL-22-429 TT genotype (OR = 1.45, 95% CI = 1.02, 2.07; P = 0.04). When stratifying by the tumor location, tumor size, growth pattern and TNM stage of colon cancer, we found no statistical association. The IL-22 + 1046 T/A and IL-22 + 1995 A/C gene polymorphisms were not associated with colon cancer. Conclusion Our findings suggested that the IL-22 -429C/T gene polymorphisms might be associated with colon cancer.