AbstractIt has been reported that polymorphisms of human leukocyte antigen (HLA) genes and several cytokine genes are associated with an increased risk of developing gastric cancer (GC). However, the results of studies from different geographic regions, ethnic groups and study groups are inconsistent. The aim of this study was to evaluate the influence of H. pylori infection and host genetic factors on GC susceptibility in Japanese patients with GC. We analyzed genotypes for HLA class I and II, tumor necrosis factor α, interleukin (IL)‐1β, IL‐1 receptor, IL‐4, IL‐4Rα and IL‐10 in 330 H. pylori‐infected noncardia patients with GC and 190 H. pylori‐infected nonulcer dyspeptic controls. Haplotype analyses indicated that the frequencies of the HLA DRB1*0405 and DQB1*0401 alleles were increased in the patients with intestinal‐type GC when compared with controls (both DRB1*0405 and DQB1*0401: p = 0.015, OR = 1.57, 95% CI = 1.09–2.26), but the changes were not statistically significant after correction for multiple comparisons. None of the cytokine gene polymorphisms were associated with GC susceptibility, whether patients with GC were analyzed as a group according to the histological subtype. Of interest was the comparison of controls and patients with intestinal‐type GC. The frequency of an IL‐10‐592AA homozygote showing concomitant carriage of the HLA DRB1*0405‐DQB1*0401 haplotype was significantly higher in patients with intestinal‐type GC (χ2 = 6.369, p = 0.0116, pc = 0.0464, OR = 2.43, 95% CI = 1.21–4.48). Our results suggest that the HLA class II and IL‐10‐592A/C polymorphisms synergistically affect the susceptibility to GC development of H. pylori‐infected individuals in the Japanese population. © 2009 UICC