Homozygous (PIZZ) alpha‐1‐antitrypsin (α₁‐AT) deficiency is associated with the development of liver damage in children as well as chronic liver injury and hepatocellular carcinoma in adults. The α₁‐AT mutant Z gene encodes a mutant protein that accumulates in the endoplasmic reticulum of hepatocytes rather than being secreted appropriately into serum. Liver injury is caused by the accumulation of α₁‐AT mutant Z protein in hepatocytes, which triggers downstream intracellular injury pathways. However, development of clinical liver disease among PIZZ homozygotes is highly variable, suggesting other genetic or environmental factors contribute to liver injury. In this study, we tested whether nonsteroidal anti‐inflammatory drugs (NSAIDs) could be a comorbid factor in the development of liver injury in α₁‐AT deficiency using the PiZ mouse. This mouse model is transgenic for the mutant Z allele of the human α₁‐AT gene, in which α₁‐ATZ expression is regulated by the human promoter regulatory sequences. Our results showed that administration of indomethacin to PiZ mice resulted in increased hepatic injury, indicated by increased hepatocellular proliferation and increased activation of caspase 9. This indomethacin‐induced injury was associated with activation of IL‐6–STAT3 signaling, increased expression of α₁‐AT mRNA, and greater accumulation of mutant polymerized α₁‐ATZ protein in livers of indomethacin‐treated PiZ mice compared to vehicle‐treated PiZ animals. In conclusion, environmental factors, such as exogenous medication administration, can significantly potentiate the liver injury associated with α₁‐ATZ hepatic accumulation; NSAIDs may be especially injurious to patients with α₁‐AT deficiency, possibly by increasing the expression and accumulation of the hepatotoxic mutant protein. (HEPATOLOGY 2006;44:976–982.)