Xenoestrogen mimics estrogen-like activities primarily based on alterations of gene expression and interactions with estrogen receptors ER and ER. However, requirement for large concentrations to induce estrogenic phenotypes and low affinity for ERs have challenged the notion that prevailing xenoestrogens are significant health hazards. Here, in this study we show that under certain conditions, exposure of xenoestrogen could be potentially harmful in respect of enhanced uterine estrogenicity. Previously, we have demonstrated that estradiol-17 (E₂) upregulates uterine Bip, a stress-related endoplasmic reticulum protein, via ER-independent mechanism in mice. Moreover, this protein essentially involves in E₂-mediated uterine growth response and ER-dependent gene transcription. Here, we demonstrate that among three tested xenoestrogens, only kepone (>15-30 mg/kg) exerts sustained inductive response for uterine Bip expression. Interestingly, this kepone-induced Bip strongly correlates with ER-dependent growth and gene expressional responses in the mouse uterus. Furthermore, these effects were strongly suppressed after knock-down of uterine Bip, via adenovirus approach. While, kepone at 7.5 mg/kg was not effective, but was strongly stimulatory by adenovirus-driven forced expression of uterine Bip. In contrast, the control GFP virus was not effective in above responses. Furthermore, the induction of uterine Bip by stress-related signals also revealed the onset of uterine growth in mice, when exposed to sub-lethal dose of kepone. Collectively, studies provide novel molecular evidence that Bip acts as a critical regulator to amplify estrogenic potency for a weak xenoestrogen kepone.