Several epidemiological studies have shown that the myeloperoxidase (MPO) G-463A polymorphism may influence the risk of many cancers, including lung, breast, bladder and laryngeal cancer. However, there is no study concerning the MPO polymorphism and gastric cancer risk. In this hospital-based, case-control study, we used polymerase chain reaction-restriction fragment length polymorphism protocols to examine the prevalence of MPO G-463A polymorphism in gastric cancer. A significantly different distribution of the MPO -463G/A genotype was demonstrated among the cases and controls (chi2=7.42, P=0.03). Subjects with the variant genotypes (the sum of GA and AA) had a 44% reduced risk of gastric cancer relative to those with GG [adjusted odds ratio (OR)=0.56; 95% CI: 0.32-0.97]. Stratified analyses revealed that the protective effect of A allele was significant in male (adjusted OR=0.51; 95% CI: 0.26-0.98) or younger subjects (age<58 years) (adjusted OR=0.42; 95% CI: 0.18-0.94), but not in female or older subjects. In addition, there was also a significantly reduced risk in subjects residing in rural areas (adjusted OR=0.41; 95% CI: 0.18-0.95) but not in urban areas. The interaction between the MPO G-463A polymorphism and smoking status was not observed in this study. Tumor differentiation was also not found to be associated with the MPO genotype. In conclusion, our results showed that the MPO -463 G to A variant may be associated with the decreased risk of gastric cancer in Chinese population.