Background: The mechanistic role of peroxisome proliferator-activated receptor γ (PPARγ) in chronic obstructive pulmonary disease (COPD) is poorly understood. Results: COPD and cigarette smoke exposure down-regulated PPARγ and produced inflammation that PPARγ agonists reversed through multiple pathways. Conclusion: PPARγ plays a pivotal role in COPD. Significance: PPARγ agonists may be the first effective treatment for COPD. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.