Cystic fibrosis is an inherited genetic disease caused by dysregulation of the CFTR anion channel.  Clinical manifestations of this disease include chronic mucus plugging of the airways and unrelenting cycles of infection and inflammation.  CFTR^-/- transgenic mice which lack functional CFTR do not develop CF-like lung disease.  Accordingly, mice overexpressing the beta subunit of the epithelial Na⁺ channel (ßENaC mice) were generated. These mice spontaneously develop CF-like lung disease and exhibit significant mortality.  Orai1 is a plasma membrane Ca²⁺ channel that regulates inflammation. Orai1 activity is increased in CF airways.  We hypothesized that Orai1 inhibition would reduce inflammation in the ßENaC mice. Accordingly, we developed an Orai1-specific peptide antagonist called ELD607. Our HPLC data indicated that ELD607 was stable in proteolytically-rich CF sputum and our quartz crystal microbalance with dissipation (QCMD) data indicated that ELD607 did not stick to mucus.  We added ELD607 (0.5 mg/kg) or vehicle (saline) to ßENaC mice and their WT littermate controls daily for 10 days.  We assessed survival over 10 days and surviving mice were sacrificed in order to perform Ussing chamber studies and lung histology.  Amiloride-sensitive currents were significantly elevated in ßENaC mice relative to WT mice (n=3 per group).  However, chronic ELD607 dosing had no effect on either isoprenaline or amiloride-sensitive currents (markers of CFTR and ENaC activity respectively) in either WT or ßENaC mice (all n=3 per group).  After 10 days, 100% of WT mice survived, regardless of treatment, while 50% of ßENaC mice survived.  Importantly, 10 days of ELD607 exposure, significantly increased ßENaC mouse survival to 95%. In these mice, lung neutrophilia was reduced by 90% (n=9/group) while lung macrophage levels were restored to the normal range. Thus, we tentatively conclude that despite not altering ENaC activity, ELD607 increases survival by reducing neutrophilia and preventing lung damage. Such an approach may be useful for the treatment of CF lung disease by treating CF inflammation.