Interleukin (IL)-22, a relatively new member of the IL-10 family, has been implicated in inflammation and tumorigenesis. The aim of this study was to identify genetic polymorphisms in IL-22 and to measure plasma levels of IL-22 in patients with nonsmall cell lung cancer (NSCLC). Patients with NSCLC had a significantly higher frequency of IL-22 rs2227484 CT genotype (odds ratio [OR]=1.917, 95% confidence interval [CI] 1.001-3.670, p=0.038) and T allele (OR=1.878, 95% CI 1.010-3.491, p=0.049) as compared with controls. The rs2227484 genotype was associated with a 2.263-fold increased risk for advanced NSCLC (p=0.041). Among different subtypes of NSCLC, these associations were more obvious in the adenocarcinoma. Moreover, patients with high frequencies of genotypic polymorphisms had high plasma levels of IL-22. IL-22 polymorphisms and corresponding high levels of IL-22 in plasma may contribute to the development of NSCLC, especially adenocarcinoma.