Rationale: Oxidative stress is a key contributor in COPD pathogenesis caused by cigarette smoking. NRF2, a redox-sensitive transcription factor dissociates from its inhibitor KEAP1 to induce antioxidants that inhibits oxidative stress. Objectives: To determine the link between COPD severity, oxidative stress and NRF2-dependent antioxidant levels in peripheral lung tissue from COPD patients. Methods: We assessed the expression of NRF2, NRF2-dependent antioxidants, NRF2 regulators and oxidative damage in non-COPD (smokers and former smokers) and smoker COPD lung tissues (mild and advanced). Cigarette smoke exposed human lung epithelial cells (Beas2B) and mice were used to understand the mechanisms. Results: When compared to non-COPD lungs, the COPD patient lung tissues show i) marked decline in NRF2-dependent antioxidants and glutathione levels; ii) increased oxidative stress; iii) significant decrease in NRF2 protein with similar NRF2 mRNA levels; iv) similar KEAP1 but significantly decreased DJ-1 levels (a protein that stabilizes NRF2 protein by impairing KEAP1-NRF2 association). Cigarette smoke exposure to Beas2B cells caused oxidative modification and proteasomal degradation of DJ-1 protein. Disruption of DJ-1 in mouse lungs, mouse embryonic fibroblasts and Beas2B cells lowered NRF2 protein stability and impaired antioxidant induction in response to cigarette smoke. Interestingly, targeting KEAP1 by siRNA or small molecular activator, sulforaphane restored induction of NRF2-dependent antioxidants in DJ-1 disrupted cells in response to cigarette smoke. Conclusions: NRF2-dependent antioxidants and DJ-1 expression was negatively associated with severity of COPD. Therapy directed towards enhancing NRF2-regulated antioxidants may be a novel strategy for attenuating the effects of oxidative stress in COPD pathogenesis.