Background Bisphenol A ( BPA ) is a base chemical used extensively in many consumer products. BPA has recently been associated with increased risk of cardiovascular disease ( CVD ) in multiple large‐scale human population studies, but the underlying mechanisms remain elusive. We previously reported that BPA activates the pregnane X receptor ( PXR ), which acts as a xenobiotic sensor to regulate xenobiotic metabolism and has pro‐atherogenic effects in animal models upon activation. Interestingly, BPA is a potent agonist of human PXR but does not activate mouse or rat PXR signaling, which confounds the use of rodent models to evaluate mechanisms of BPA ‐mediated CVD risk. This study aimed to investigate the atherogenic mechanism of BPA using a PXR ‐humanized mouse model. Methods and Results A PXR ‐humanized ApoE deficient (hu PXR •ApoE ^−/− ) mouse line was generated that respond to human PXR ligands and feeding studies were performed to determine the effects of BPA exposure on atherosclerosis development. Exposure to BPA significantly increased atherosclerotic lesion area in the aortic root and brachiocephalic artery of hu PXR •ApoE ^−/− mice by 104% ( P <0.001) and 120% ( P <0.05), respectively. By contrast, BPA did not affect atherosclerosis development in the control littermates without human PXR . BPA exposure did not affect plasma lipid levels but increased CD 36 expression and lipid accumulation in macrophages of hu PXR •ApoE ^−/− mice. Conclusion These findings identify a molecular mechanism that could link BPA exposure to increased risk of CVD in exposed individuals. PXR is therefore a relevant target for future risk assessment of BPA and related environmental chemicals in humans.