Treatment of acute lung injury (ALI) remains an unsolved problem in intensive care medicine. Activation and recruitment of neutrophils are regarded as key mechanisms in the progression of ALI. As pioglitazone holds potent pleiotropic anti-inflammatory effects, we explored its effects during ALI.C57Bl/6 mice were exposed to aerosolised lipopolysaccharides (LPSs) (500 ?g•mL?1) and their alveolar, interstitial and intravascular neutrophils were assessed 4 h later. Lung permeability changes were evaluated by fluorescein isothiocyanate-dextran clearance and protein content in the bronchoalveolar lavage fluid. In vitro, human isolated neutrophils were pretreated with piolitazone (10 ?M, for 1 or 3 h) and then activated with N-formyl-l-methionyl-l-leucyl-l-phenylalanine. Neutrophil activation, adhesion, release and formation of reactive oxygen species (ROS) and phagocytosis were measured thereafter.Pioglitazone treatment before or after induction of ALI significantly diminished alveolar (reduction by 73% and 67%, respectively) and interstitial neutrophil influx (reduction by 55% and 63%, respectively) and reduced lung permeability changes (reduction by 64% and 58%, respectively) indicating a protective role of pioglitazone treatment in ALI. Moreover, pioglitazone significantly reduced degranulation and adhesion of neutrophils without affecting ROS formation and release or bacterial phagocytosis.Pioglitazone reduces recruitment and activation of neutrophils thereby preventing LPS-induced ALI. Our results imply a potential role for pioglitazone treatment in the management of ALI.