Duodenal gastric heterotopia (DGH) is a benign asymptomatic condition assumed to be of congenital origin. Since DGH is often associated with fundic gland polyps (FGPs) that frequently carry a somatic β-catenin gene mutation, we examined whether DGH, either sporadic or FGP-associated, is attributable to alterations of the Wnt/β-catenin pathway. Genetic analysis revealed frequent somatic β-catenin gene mutations in DGH; some of which showed the same mutation pattern as coexisting FGPs. All missense mutations were confined to codons 32, 33, and 37. No such mutations were observed, however, in any of the specimens from focal gastric foveolar metaplasia (GFM). Therefore, DGH is not a mere congenital lesion due to aberrant migration of normal gastric mucosa or a simple reactive metaplasia after regenerative stimuli of the duodenal mucosa, but a distinct condition based upon molecular genetic changes in the Wnt/β-catenin pathway.