The proinflammatory cytokine interleukin-1 has been implicated in host susceptibility to Helicobacter pylori-associated disease. Recent studies suggest that this susceptibility may be under genetic control. It remains to be determined whether the relationship between IL-1 gene polymorphism and gastrointestinal disease in patients with H. pylori infection is due to the role of IL-1 in determining susceptibility to H. pylori infection per se or to the development of distinct pathological lesions. The aim of this study was to prospectively investigate the relationship between selected polymorphisms in three of the major IL-1 gene family members, seeking associations with H. pylori infection and/or gastric cancer. A total of 559 individuals were studied: 191 patients attending for gastroscopy, 98 with current or previous H. pylori, an additional 79 patients with gastric cancer, and 289 healthy controls. The major novel finding of the study was a marked difference in the genotype frequencies for the IL1R1 Hinfl SNP in those with current or previous evidence of H. pylori compared to those without. (GG, 53 vs 75%; GA, 40 vs 19%; AA, 7 vs 6%; P = 0.0079). The association indicates an increased risk of H. pylori infection or persistence in those with the IL1R1 Hinfl A allele (0.27 vs 0.156; P = 0.009; OR = 2.01). Our results suggest that the relationship among IL-1 gene polymorphism, H. pylori, and disease is more complex than initially proposed. More detailed studies of the IL-1 gene cluster are needed.