Background: High-dose ibuprofen is clinically effective in cystic fibrosis (CF); however, its molecular mechanisms are poorly understood. Objective: To test the hypothesis that clinically relevant concentrations of ibuprofen suppress activation of nuclear factor (NF)-ĸB and thus down-regulate stimulated interleukin (IL)-8 production in CF respiratory epithelial cells. Methods: The majority of experiments were conducted in CFTE29o– cells (F508del-mutated CF transmembrane regulator, CFTR). Key experiments were confirmed in CFBE41o– cells (F508del-mutated CFTR) and 1HAEo– cells (wild-type CFTR). NF-ĸB and IL-8 were stimulated with tumour necrosis factor (TNF)-α or IL-1β. NF-ĸB and IL-8 suppression by ibuprofen (480 µM) was compared to dexamethasone (5 nM). Results: Both TNF-α and IL-1β activated NF-ĸB and stimulated IL-8 production. Both ibuprofen and dexamethasone demonstrated comparably modest suppression of NF-ĸB transcriptional activity. However, ibuprofen had no effect on stimulated IL-8 mRNA and protein. By contrast, dexamethasone significantly down-regulated stimulated IL-8 mRNA and protein. Conclusions: The present data do not support the hypothesis that ibuprofen down-regulates IL-8 production in response to TNF-α and IL-1β in CF respiratory epithelium. Suppression of NF-ĸB transcriptional activity does not discriminate between anti-inflammatory drugs with or without effects on IL-8 production. We speculate that NF-ĸB-independent mechanisms may be responsible for anti-IL-8 effects of dexamethasone.