The pathophysiology of cystic fibrosis (CF) inflammatory lung disease is not well understood. CF airway epithelial cells respond to inflammatory stimuli with increased production of proinflammatory cytokines as a result of increased NFB activation. Peroxisome proliferator-activated receptor gamma (PPAR) inhibits NFB activity and is reported to be reduced in CF. If PPAR participates in regulatory dysfunction in the CF lung, perhaps PPAR ligands might be useful therapeutically. Cell models of CF airway epithelium were used to evaluate PPAR expression and binding to NFB at basal and under conditions of inflammatory stimulation by Pseudomonas aeruginosa or TNF/IL-1. An animal model of CF was used to evaluate the potential of PPAR agonists as therapeutic agents in vivo. In vitro, PPAR agonists reduced IL-8 and MMP-9 release from airway epithelial cells in response to PAO1 or TNF/IL-1 stimulation. Less NFB bound to PPAR in CF than normal cells, in two different assays; PPAR agonists abrogated this reduction. PPAR bound less to its target DNA sequence in CF cells. To test the importance of the reported PPAR inactivation by phosphorylation, we observed that inhibitors of ERK, but not JNK, were synergistic with PPAR agonists in reducing IL-8 secretion. In vivo, administration of PPAR agonists reduced airway inflammation in response to acute infection with P. aeruginosa in CF, but not wild type, mice. In summary, PPAR inhibits the inflammatory response in CF, at least in part by interaction with NFB in airway epithelial cells. PPAR agonists may be therapeutic in CF.