Cigarette smoke is the main cause of Chronic Obstructve Pulmonary Disease (COPD), where it can contribute to the observed airway inflammation. Prostaglandin E₂ (PGE₂) is produced within human airways, and both pro-and anti-inflammatory activities have been reported. We quantitated PGE₂ concentrations in induced sputum supernatants from different groups of subjects and we correlated the obtained values to neutrophil infiltration, as well as to the expression of cyclooxygenase-2 (COX-2). Cigarette smoke extract (CSE) was used to evaluate the effect of smoking on COX-2 and PGE₂ receptor expression as well as on PGE₂ release in neutrophils and alveolar macrophages (AM) obtained from normal donors. The effect of PGE₂ and of PGE receptor agonists and antagonists were evaluated on the adhesion of neutrophil to a human bronchial epithelial cell line (16HBE). PGE₂ levels, COX-2 expression and neutrophil infiltration were significantly higher in normal smokers and COPD smokers (p<0.0001) when compared to controls and COPD former smokers. Induced sputum supernatant caused neutrophil adhesion to 16HBE that was significantly reduced, in COPD smokers only, by PGE₂ immunoprecipitation. In vitro experiments confirmed that CSE increased PGE₂ release, COX-2 and PGE₂ receptors expression in neutrophils and AM; PGE₂ enhanced the adhesion of neutrophils to 16HBE and a specific EP4 receptor antagonist blunted its effect. These results suggest that CSE promote the induction of COX-2 and contributes to the proinflammatory effects of PGE₂ in the airways of COPD subjects.