Leukotriene B 4 (LTB 4) contributes to many inflammatory diseases, including genetic and nongenetic forms of chronic obstructive pulmonary disease. α-1 Antitrypsin (AAT) deficiency (AATD) is characterized by destruction of lung parenchyma and development of emphysema, caused by low AAT levels and a high neutrophil burden in the airways of affected individuals. In this study we assessed whether AATD is an LTB 4-related disease and investigated the ability of serum AAT to control LTB 4 signaling in neutrophils. In vitro studies demonstrate that neutrophil elastase is a key player in the LTB 4 inflammatory cycle in AATD, causing increased LTB 4 production, and associated BLT1 membrane receptor expression. AATD patients homozygous for the Z allele were characterized by increased neutrophil adhesion and degranulation responses to LTB 4. We demonstrate that AAT can bind LTB 4 and that AAT/LTB 4 complex formation modulates BLT1 engagement and downstream signaling events, including 1, 4, 5-triphosphate production and Ca 2+ flux. Additionally, treatment of ZZ-AATD individuals with AAT augmentation therapy decreased plasma LTB 4 concentrations and reduced levels of membrane-bound neutrophil elastase. Collectively, these results provide a mechanism by which AAT augmentation therapy impacts on LTB 4 signaling in vivo, and not only reinforces the utility of this therapy for resolving inflammation in AATD, but supports useful future clinical applications in treatment of other LTB 4-related diseases.