The objective of this study is to determine whether polymorphisms in the lymphotoxin-α (LTA) and interleukin-10 (IL-10) genes were associated with gastric cancer (GC) in a Chinese population. One hundred ninety-six patients with GC and 248 healthy individuals were enrolled in this case-control study. The LTA 252G was associated with an increased risk of GC, with an adjusted odds ratio (OR) of 1.74 (95% confidence interval [CI]: 1.12-2.69) for the LTA 252G heterozygotes and 2.42 (95% CI: 1.28-4.58) for the LTA 252G homozygotes as compared with noncarriers. In contrast, such association is not found in polymorphisms in IL-10; however, a potential interaction between LTA +252 G allele and IL-10-1082 G/A was found to be associated with the occurrence of GC (adjusted OR: 1.91; 95% CI: 1.01-3.64). This study indicates that the LTA +252G allele is associated with increased risk for the presence of GC in a Helicobacter pylori infection positive subgroup and potential interaction between IL-10 and LTA may contribute to the risk of GC.