Gastric fundic gland polyps (FGPs) are considered hamartomas, and various gastrointestinal hamartomas are associated with tuberous sclerosis complex (TSC). The aim of this study was to investigate a possible link between TSC proteins (hamartin and tuberin) and sporadic FGPs. We examined 33 sporadic FGPs and 26 biopsies of normal fundic mucosa by immunohistochemistry. Nuclear immunoreactivity for tuberin was dramatically reduced or lost in most sporadic FGPs, and tuberin unexpectedly accumulated in the cytoplasm in oxyntic glands. About 18% (6/33) of FGPs were immunopositive in an average of 1.7% of oxyntic cell nuclei, compared with 77% (20/26) of controls in an average of 24.4% of oxyntic cell nuclei (P < .01). No change in hamartin was noted. We further examined the tuberin-associated proteins glucocorticoid receptor (GCR) and p27. Nuclear immunoreactivity for GCR was lost in most sporadic FGPs, but p27 distribution was normal. Sporadic FGPs had a low frequency of staining for Ki-67 except for some cells from cystic components, which is consistent with their slow growth. Our results are consistent with the hypothesis that tuberin may play an important role in pathogenesis of sporadic FGPs. First, an altered cellular localization of tuberin may lead to the deregulation of cell proliferation by interrupting its interaction with hamartin. Second, altered cellular localization of tuberin may preclude its negative regulation of gene transcription mediated by GCR.