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Background: Chronic obstructive pulmonary disease (COPD) is associated with an abnormal inflammatory response of the lungs to cigarette smoke (CS). The products of CS oxidatively modify proteins thereby inducing severe oxidative cellular damage. The ubiquitin proteasome system serves as the major disposal system for oxidatively modified proteins and is thus essential for proper cellular function. However, its role in CS-induced cell damage is currently unknown. We hypothesized that CS exposure impairs the function of the proteasome resulting in accumulation of oxidatively modified proteins, and exacerbation of cellular stress. Methods and Results: Treatment of human lung epithelial cells with CSE resulted in time and dose-dependent decrease of survival and increase of intracellular reactive oxygen species. The increased levels of oxidative stress correlated with accumulation of oxidatively modified proteins. CSE exposure also induced accumulation of polyubiquitinated proteins. Notably, treatment with CSE significantly impaired all three proteasomal activities at high doses. The trypsin-like activity was also inhibited at nontoxic CSE doses. Expression of the proteasome was unaffected. To confirm these observations in vivo, mice were exposed for 3 days to CS. Importantly, the trypsin-like activity of the proteasome was significantly reduced in lungs of smoked mice. We also observed increased levels of polyubiquitinated proteins in tissue extracts of smoked lungs compared controls. Conclusion: Our data clearly indicate that acute cigarette smoke exposure impairs proteasome function in the lung. Reduced proteasomal protein degradation might thus contribute to the detrimental cellular effects of cigarette smoke exposure in COPD.