Rationale: Cystic fibrosis (CF) is associated with severe neutrophilic airway inflammation. We showed that moxifloxacin (MXF) inhibits IL-8 and MAPK activation in monocytic and respiratory epithelial cells. Azithromycin (AZM) and ciprofloxacin (CIP) are used clinically in CF. Thus, we now examined effects of MXF, CIP and AZM directly on CF cells. Methods: IB3, a CF bronchial cell line, and corrected C38 cells were treated with TNF-, IL-1 or LPS with or without MXF, CIP or AZM, 5-50 µg/ml. IL-6 and IL-8 secretion (ELISA), MAPK’s ERK 1/2, JNK, p38 and nuclear p65 NF-B (WB) activation were measured. Results: Baseline IL-6 was 6-fold higher in IB3 than C38 cells but IL-8 was similar. TNF-and IL-1 increased IL-6 and IL-8 12-67 fold with higher levels in IB3 than C38 cells post TNF- (p<0.05). Levels were unchanged following LPS. Baseline p-ERK1/2, JNK and nuclear NF-B p65 were higher in IB3 than C38 cells (5-, 1.4- and 1.4-fold) and following TNF- increased, as did p-p38, by 1.6- to 2-fold. MXF 5-50µg/ml and CIP 50µg/ml, but not AZM, suppressed IL-6 and IL-8 secretion by up to 69%. MXF inhibited TNF- stimulated MAPK’s ERK1/2, 46kDa JNK and NF-B up to 60%, 40% and 40% respectively. In contrast, MXF did not inhibit p38 activation, implying a highly selective pre-translational effect. Conclusion: TNF- and IL- induce an exaggerated inflammatory response in CF airway cells, inhibited by MXF more than by CIP or AZM. Clinical trials are recommended to assess efficacy in CF and other chronic lung diseases.