With an estimate of 380 000 new cases each year, gastric cancer (GC) is one of the most frequently occurring cancers in China. Genes encoding proinflammatory and anti-inflammatory cytokines are good candidates for the study of susceptibility to GC. We tested the hypothesis that the polymorphisms of interleukin 1B (IL-1B) and IL-1RN contribute toward host susceptibility to GC. In a matched case-control design, we enrolled 308 pairs of GC and control participants between October 2010 and August 2011. We sequenced IL-1B +3954 C/T, IL-1RN -9876 G/A, -9739 A/G, and IL-1RN -9091 A/C using MALDI-TOF MS and collected demographic data as well as lifestyle factors using a questionnaire. GC patients reported statistically significantly greater proportions with family history of cancer (29.9 vs. 10.7%, P<0.01) and alcohol drinking (54.5 vs. 43.2%, P<0.01) than the controls. The proportion of irregular eaters was statistically higher among the patients than among the controls (66.7 vs. 24.4%, P<0.01). The IL-1B +3954 CT or the TT variant genotype was statistically significantly associated with a risk of GC [adjusted odds ratio (OR), 2.94; 95% confidence interval (CI), 1.06-8.15], whereas variants of IL-1RN -9876 G/A, IL-1RN -9739 A/G, and IL-1RN -9091 A/C were not associated (adjusted OR, 1.29, 95% CI, 0.77-2.16; adjusted OR, 1.25, 95% CI, 0.75-2.07; adjusted OR, 1.09, 95% CI, 0.71-1.67, respectively). Haplotypes established from the three polymorphisms of IL-1RN were not associated with a risk of GC. The IL-1B +3954 C/T polymorphism is associated with a risk of GC in our study. Lifestyle and environmental factors such as drinking, eating irregularly, and family history of cancer increase the risk.