Cigarette smoking results in oxidative stress and inflammation in the lungs, which are involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). 4-Hydroxy-2-nonenal (4-HNE), a highly reactive diffusible product of lipid peroxidation, is a key mediator of oxidant-induced cell signaling and apoptosis. 4-HNE has a high affinity toward cysteine, histidine, and lysine groups and forms direct protein adducts. We investigated the presence of 4-HNE–modified proteins in lung tissue obtained from subjects with and without COPD. We studied 23 current or ex-smokers with similar smoking histories with COPD (n = 11; FEV₁ < 70% predicted) or without COPD (n = 12; FEV₁ > 84% predicted) who had undergone lung resection. As 4-HNE and transforming growth factor-β₁ (TGF-β₁) can modulate γ-glutamylcysteine synthetase (γ-GCS) mRNA levels in lung cells, we assessed the relations between 4-HNE–modified protein levels, FEV₁, γ-GCS, and TGF-β₁. 4-HNE–modified protein levels were elevated in airway and alveolar epithelial cells, endothelial cells, and neutrophils in subjects with COPD, compared with the levels in subjects without COPD (p < 0.01). We also observed a significant inverse correlation between the levels of 4-HNE adducts in alveolar epithelium, airway endothelium, and neutrophils and FEV₁ (p < 0.05) and a positive correlation between 4-HNE adducts and TGF-β₁ protein and mRNA as well as γ-GCS mRNA levels in airway and alveolar epithelium (p < 0.01). The elevated levels of 4-HNE may play a role in the signaling events in lung inflammation leading to the imbalance of the expression of both proinflammatory mediators and protective antioxidant genes in COPD.