We investigated the association of Interleukin (IL)-6-6331 polymorphisms with susceptibility to gastric cancer in 375 patients with gastric cancer and 386 age- and gender-matched healthy controls. After adjustment for the potential confounding effects of gender and age, IL-6-6331TC genotype was associated with a decreased risk of gastric cancer compared with the CC genotype. Further stratification analyses indicated that the protective effect of TC genotype was also observed in poorly differentiated gastric cancer, noncardia gastric cancer, and intestinal-type gastric cancer, respectively. These results suggest that the IL-6-6331 polymorphism is involved in susceptibility to developing gastric cancer.