Mutant α1-antitrypsin Z (α1-ATZ) protein, which has a tendency to form aggregated polymers as it accumulates within the endoplasmic reticulum of the liver cells, is associated with the development of chronic liver injury and hepatocellular carcinoma in hereditary α1-antitrypsin (α1-AT) deficiency. Previous studies have suggested that efficient intracellular degradation of α1-ATZ is correlated with protection from liver disease in α1-AT deficiency and that the ubiquitin-proteasome system accounts for a major route, but not the sole route, of α1-ATZ disposal. Yet another intracellular degradation system, autophagy, has also been implicated in the pathophysiology of α1-AT deficiency. To provide genetic evidence for autophagy-mediated disposal of α1- ATZ, here we used cell lines deleted for the Atg5 gene that is necessary for initiation of autophagy. In the absence of autophagy, the degradation of α1-ATZ was retarded, and the characteristic cellular inclusions of α1-ATZ accumulated. In wild-type cells, colocalization of the autophagosomal membrane marker GFP-LC3 and α1-ATZ was observed, and this colocalization was enhanced when clearance of autophagosomes was prevented by inhibiting fusion between autophagosome and lysosome. By using a transgenic mouse with liver-specific inducible expression of α1-ATZ mated to the GFP-LC3 mouse, we also found that expression of α1-ATZ in the liver in vivo is sufficient to induce autophagy. These data provide definitive evidence that autophagy can participate in the quality control/degradative pathway for α1- ATZ and suggest that autophagic degradation plays a fundamental role in preventing toxic accumulation of α1-ATZ.