The thioredoxin/peroxiredoxin system comprises a redox-regulated antioxidant family in human lung; its significance, regulation, or oxidation has not been evaluated in smoking-related lung diseases. Here, we present the expression of the thioredoxin/peroxiredoxin system in lung biopsies from normal lung (n = 14), smokers (n = 21), and patients with chronic obstructive pulmonary disease (COPD, n = 38), and assess the possible inactivation/oxidation of this system by nonreducing Western blotting, two-dimensional gel electrophoresis, and mass spectrometry. Our study shows that the thiol status of the Trx/Prx-system can be modulated in vitro, but it appears to have high resistance against the oxidative stress in COPD.