Cystic fibrosis (CF) is the most common inherited illness in Ireland that impacts directly on an individual’s longevity. The deltaF508 CF phenotype affects secretory epithelia in different tissues, in particular the lung, the site of chronic infection in CF. The surface mucus is a key component of the innate immune system of the respiratory tract. Proper hydration of the airway surface layer (ASL) is prerequisite for efficient mucociliary clearance of inhaled particles and pathogens. There are significant differences in the progression of CF in male and female patients termed the « CF gender gap » (1). Lung function among female patients deteriorates 26% more rapidly than in male patients and on average, male CF patients survive 9 years longer than females. Moreover, measurement of nasal trans-epithelial potential difference in female CF subjects has shown an effect of menstrual cycle stage and circulating oestrogen on ion transport properties of the epithelium (2). Confocal fluorescence microscopy was used to test the effects of 17β-Estradiol (E2) on ASL height in a normal human bronchial epithelial cell line (NuLi-1) and a deltaF508 CF cell line (CuFi-1), derived from a homozygous CFTR F508del/F508del individual. To investigate signal transduction via membrane and nuclear oestrogen receptors, we tested the effects of free E2 and a nuclear-impeded Estrogen Dendrimer Conjugate (EDC – EDC concentrations are expressed in terms of E2 equivalent) on ASL height. In control conditions, ASL height is significantly higher in normal cells than in CF cells (6.82 ± 0.53 μm versus 5.70 ± 0.21 μm, n=13, p=0.016, t test). Moreover, ASL height showed a significant decrease in both normal (25% decrease in average after E2 treatment, n=5, p<0.05, repeated measures ANOVA) and CF (20% decrease in average after E2 treatment, n=5, p<0.05, repeated measures ANOVA) cell lines after 30 min treatment using concentrations of 17β-Estradiol between 0.1 and 10 nM. Finally, experiments using equivalent concentrations of EDC showed a significant reduction of ASL in both cell lines (4.72 ± 0.25 in NuLi-1 and 4.86 ± 0.42 μm in CuFi-1 after 1 nM E2 equivalent EDC, n=5, p<0.05, repeated measures ANOVA) whereas the empty dendrimer had no significant effect on ASL height. These results demonstrate an antisecretory effect of oestrogen in both normal and CF bronchial epithelia which results in a reduction of ASL height. These rapid responses to oestrogen are initiated by membrane-initiated signalling events rather than via the classical nuclear receptor signal transduction pathway.