Leukotriene A₄ hydrolase (LTA₄H) is a proinflammatory enzyme that generates the inflammatory mediator leukotriene B₄ (LTB₄). LTA₄H also possesses aminopeptidase activity with unknown substrate and physiological importance; we identified the neutrophil chemoattractant proline-glycine-proline (PGP) as this physiological substrate. PGP is a biomarker for chronic obstructive pulmonary disease (COPD) and is implicated in neutrophil persistence in the lung. In acute neutrophil-driven inflammation, PGP was degraded by LTA₄H, which facilitated the resolution of inflammation. In contrast, cigarette smoke, a major risk factor for the development of COPD, selectively inhibited LTA₄H aminopeptidase activity, which led to the accumulation of PGP and neutrophils. These studies imply that therapeutic strategies inhibiting LTA₄H to prevent LTB₄ generation may not reduce neutrophil recruitment because of elevated levels of PGP.