Background: Polymorphisms of genes encoding cytokines could be potential biomarkers to predict risk ofgastric cancer (GC). Here, we investigated the association between the IL-6 -6331 (T/C, rs10499563) polymorphismin its promoter region and GC risk. Methods: In this case-control study of 215 GC cases and 518 non-cancercontrols, the IL-6 -6331 (T/C, rs10499563) polymorphism was genotyped by polymerase chain reaction-restrictionfragment length polymorphism (PCR-RFLP). Results: Individuals with the TC or CC genotype were associatedwith a significantly decreased risk of GC (OR=0.710, 95%CI: 0.504-0.999, P=0.049) compared with TT wild-typecarriers. Ther C allele was also associated with significantly decreased risk of GC (OR=0.715, 95%CI: 0.536-0.954, P=0.023) compared with the T allele. In the stratification analysis, TC or CC genotypes were associatedwith significantly decreased GC risk in subgroups of males, people older than 60, and H. pylori-positive cases.However, no significant interaction was observed for TC or CC genotypes with H. pylori infection. On stratificationwith the Lauren classification, TC or CC genotypes were associated with significantly decreased risk of diffusetypeGC (OR=0.497, 95%CI: 0.266-0.925, P=0.027), also in subgroups of males, people older than 60, and H.pylori-positive cases. Conclusions: The IL-6 -6331 (T/C, rs10499563) polymorphism is associated with geneticsusceptibility of GC and may have the potential to predict GC risk.