Although inflammatory changes in the gastric mucosa are commonly observed in Japanese patients with functional dyspepsia (FD), detailed data regarding the relationship between the genetic regulatory factors of inflammation and FD are not available. Superoxide has been implicated in the pathogenesis of Helicobacter pylori-related diseases through inflammation. Nicotinamide adenine dinucleotide phosphate oxidase, a major source of superoxide generation plays a critical role in H. pylori-related gastric inflammation. We aimed to clarify the association between C242T polymorphism of p22PHOX, an essential component of nicotinamide adenine dinucleotide phosphate oxidase and FD in a Japanese population. Eighty-nine FD according to Rome III criteria and 95 asymptomatic participants enrolled in this study. The p22PHOX C242T polymorphism was determined by polymerase chain reaction restriction fragment length polymorphism. H. pylori infection status was examined by histology or antibody against H. pylori. Nonsignificant correlation was found between p22PHOX polymorphism and FD. In H. pylori positives, however, C242T carriers significantly associated lower risk of FD (25.9 vs. 6.2%; C/C vs. T carriers; odds ratio=0.19, 95% confidence interval=0.05-0.71, P=0.009). This significant association remained after logistic regression analysis with adjustment for sex and age (odds ratio=0.20, 95% confidence interval=0.05-0.73). No significant correlation was found between p22PHOX polymorphism and a different subgroup of FD. Our data suggest that C242T carriers status is inversely related to the risk of FD in H. pylori-infected patients.