AIM: Inducible nitric oxide synthase (iNOS) plays a central role in the pathway of reactive oxygen and nitrogen species metabolism when Helicobacter pylori ( H pylori) infection occurs in humans. iNOS Ser608 Leu allele, a novel genetic polymorphism (C/T) occurring within exon 16 of the iNOS reductase domain, may have a dramatic effect on the enzymatic activity. The aim of this study was to determine whether iNOS C/T polymorphism was associated with increased susceptibility to gastric cancer.METHODS: We conducted a population based case-control study in a high gastric cancer incidence area, Yangzhong,China. Questionnaires from 93 patients with intestinal type gastric cancer (IGC), 50 with gastric cardia cancer (GCC)and 246 healthy controls were obtained between 1997 and1998, and iNOS genotyping was carried out. Odds ratios(ORs), interaction index (γ), and 95% confidence intervals for the combined effects of iNOS genotype and H pylori infection, cigarette smoking or alcohol drinking were estimated.RESULTS: The frequency of (CT+TT) genotypes was higher in cases than in control group (24.48% vs23.17%), but the difference was not statistically significant. After adjusting for age and gender, past cigarette smokers with (CT+TT)genotypes had a significantly increased risk of IGC (OR = 3.62,95% CI: 1.23-10.64), while past alcohol drinkers with(CT+TT) genotypes had a significantly increased risk of GCC (OR = 3.33, 95% CI: 1.14-9.67).H pylori CagA negative subjects with (CT+TT) genotypes had a significantly increased risk of both IGC and GCC (OR = 2.19 and 3.52, respectively).CONCLUSION: iNOS Ser608Leu allele may be a potential determinant of susceptibility to cigarette -alcohol induced gastric cancer, but larger studies are needed to confirm the observations.