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Acute liver failure remains a critical clinical condition, with high mortality rates, and increased apoptosis of hepatocytes represents a key event in the cause of liver failure. Alpha-1-antitrypsin (AAT) is synthesized and secreted mainly by hepatocytes, and plasma purified AAT is used for augmentation therapy in patients with AAT deficiency. Because AAT therapy exerts antiinflammatory and immune modulatory activities in various experimental models, and it was recently suggested that AAT exerts antiapoptotic activities, we aimed to explore whether administration of AAT may represent a therapeutic strategy to treat acute liver failure in mice. Well-established preclinical models of acute liver failure such as the Jo2 FAS/CD95 activating model and models of acetaminophen and α-amanitin poisoning were used. Therapeutic effects of AAT were evaluated by monitoring animal survival, histopathological changes, measurement of caspase activity, and serum cytokine levels. Systemic treatment with AAT significantly decreased Jo2-induced liver cell apoptosis and prolonged survival of mice. Native and oxidized (lacking elastase inhibitory activity) forms of AAT were equally effective in preventing acute liver injury and showed direct inhibition of active caspase-3 and −8 in liver homogenates and in a cell-free system in vitro. Concomitantly, mice treated with AAT showed significantly lower serum levels of tumor necrosis factor alpha (TNF-α), which also paralleled the reduced activity of ADAM17 (TACE). Noticeably, the increased survival and a reduction of apoptotic hepatocytes were also observed in the α-amanitin and acetaminophen-induced liver injury mouse models. Conclusion: Our data suggest that systemic administration of AAT can be a promising therapy to treat acute liver failure and clinical studies to explore this treatment in humans should be initiated. (Hepatology 2014;59:2299–2308)