Alpha‐1 antitrypsin (α1‐AT) deficiency is the most common genetic cause of liver disease in children. The homozygous α1‐ATZ mutation (PiZZ) results in significant liver disease in 10% of all affected patients. The α1‐ATZ mutation also may lead to worse liver injury in the setting of other liver diseases such as cystic fibrosis, nonalcoholic fatty liver disease, and hepatitis C. Although cholestatic injury is common to many forms of liver disease, its effect on the PiZZ phenotype is unknown. To elucidate the interplay of cholestasis and the PiZZ phenotype, we performed bile duct ligation (BDL) on C57BL/6 mice possessing a transgenic α1‐ATZ mutation and littermate controls. PiZ transgenic mice undergoing BDL developed more liver fibrosis by quantification of Sirius red staining (P = 0.0003) and hydroxyproline (P = 0.007) than wild‐type mice after BDL. More activated hepatic stellate cells (HSCs) and apoptotic cells also were observed in the PiZ BDL model. Quantitative real time polymerase chain reaction (PCR) of the endoplasmic reticulum (ER) stress markers CHOP and GRP78 were 4‐fold and 2‐fold more up‐regulated, respectively, in PiZ BDL mice when compared with wild‐type BDL mice (P = 0.02, P = 0.02). Increased apoptosis was also noted in PiZ BDL mice by terminal deoxynucleotidyl transferase‐mediated nick‐end labeling (TUNEL) and cleaved caspase‐3 histological staining. Conclusion: PiZ transgenic mice are more susceptible to liver fibrosis induced by cholestasis from BDL. Cholestasis therefore may lead to increased fibrosis in α1‐AT deficiency, and the α1‐ATZ mutation may act as a modifier gene in patients with concurrent cholestatic liver diseases such as cystic fibrosis. (HEPATOLOGY 2007.)