Background: The estrogen receptor antagonist tamoxifen has recently been shown to cause acute gastric atrophy and metaplasia in mice. We have previously demonstrated that the outcome of Helicobacter felis infection, which induces similar gastric lesions in mice, is altered by deletion of specific NF-κB subunits. Nfkb1-/- mice developed more severe gastric atrophy than wild-type (WT) mice 6 weeks after H. felis infection. In contrast, Nfkb2-/- mice were protected from this pathology. We therefore hypothesized that gastric lesions induced by tamoxifen may be similarly regulated by signaling via NF-κB subunits. Methods: Groups of 5 female C57BL/6 (WT), Nfkb1-/-, Nfkb2-/- and c-Rel-/- mice were administered 150mg/kg tamoxifen by IP injection. 72 hours later, gastric corpus tissues were taken for quantitative histological assessment. In addition, groups of 6 female WT and Nfkb1-/- mice were exposed to 12Gy γ-irradiation. Gastric epithelial apoptosis was quantified 6 and 48 hours after irradiation. Results: tamoxifen induced gastric epithelial lesions in all strains of mice, but this was more severe in Nfkb1-/- mice than WT mice. Nfkb1-/- mice exhibited more severe parietal cell loss than WT mice, had increased gastric epithelial expression of Ki67 and had an exaggerated gastric epithelial DNA damage response as quantified by γH2AX. To determine investigate whether the difference in gastric epithelial DNA damage response of Nfkb1-/- mice was unique to tamoxifen induced DNA damage, or a generic consequence of DNA damage, we also assessed gastric epithelial apoptosis following γ-irradiation. 6 hours after γ-irradiation, gastric epithelial apoptosis was increased in the gastric corpus and antrum of Nfkb1-/- mice. Conclusions: NF-κB1 mediated signaling regulates the development of gastric mucosal pathology following tamoxifen administration. This is associated with an exaggerated gastric epithelial DNA damage response. This aberrant response appears to reflect a more generic sensitization of the gastric mucosa of Nfkb1-/- mice to DNA damage.