Rationale: Emphysema is mainly known for the complex inflammatory processes associated with its development. In addition to lung inflammation, it is now accepted that increased alveolar cell apoptosis is also part of emphysema pathophysiology. However, little is known about the mechanisms involved in alveolar apoptosis. We postulate that oxidative stress and pro-inflammatory cytokines could lead to p53 accumulation, Bax/Bcl-x_L ratio elevation and higher TNF-related apoptosis-inducing ligand (TRAIL) receptor levels in the emphysematous lung. Objectives: To evaluate the expression of p53, Bax, Bcl-x_L, TRAIL, and TRAIL receptors in lung parenchyma from non-emphysematous non-smokers and smokers and emphysematous smokers and ex-smokers and to determine whether hydrogen peroxide (H₂O₂) and/or TNF can modulate the expression of these apoptotic proteins. Methods: p53, Bax, Bcl-x_L, and TRAIL receptor protein levels in lung parenchyma were measured by Western blot and TRAIL mRNA levels were measured by real-time PCR. Changes in TRAIL receptor, Bax, Bcl-x_L, and p53 protein levels following in vitro H₂O₂ and/or TNF stimulation of A549 cells were also assessed by Western blot. Main Results: p53 protein levels, the Bax/Bcl-x_L ratio, and TRAIL-R1, R2, R3 protein levels were significantly higher in subjects with emphysema. Moreover, they were also increased following H₂O₂ and TNF treatments of A549 cells. Conclusions: These findings suggest that oxidative stress and pro-inflammatory cytokines may be involved in the elevation of p53 levels, the Bax/Bcl-x_L ratio, and TRAIL receptor levels, new mechanisms that may be implicated in the increased alveolar cell apoptosis that occurs in emphysema.