Recent studies showed that IL-22 plays a protective role in the host defense. However, the contribution of polymorphisms of the IL-22 gene to human TB susceptibility remains untested. We have designed a computational approach to select functional SNPs in the IL-22 gene and genotyped them in a two-stage case-control study in Chinese (479 cases and 358 controls). We found that rs2227473, an SNP in the promoter region of IL-22, is associated with TB susceptibility at both stages of our study. The SNP shows associations with p-values of 0.028 and 0.034 respectively, and a combined p-value of 0.0086, with odds ratio at 0.65 (95% confidence interval 0.45-0.90). We further validated the association with an independent cohort (413 cases and 241 controls in Chinese). Our functional studies showed that patients with A allele have significantly higher IL-22 expression than those without A allele under both non-specific and specific stimulations.