Background.?Seasonal and pandemic influenza are significant public health concerns. Influenza stimulates respiratory epithelial Cl^- secretion via the cystic fibrosis transmembrane conductance regulator (CFTR). The purpose of this study was to determine the contribution of this effect to influenza pathogenesis in mice with reduced CFTR activity.Methods.?C57BL/6-congenic mice heterozygous for the F508del CFTR mutation (HETs) and wild-type (WT) controls were infected intranasally with 10,000 FFU/mouse influenza A/WSN/33 (H1N1). Body weight, arterial O₂ saturation, and heart rate were monitored daily. Pulmonary edema and lung function parameters were derived from wet:dry weight ratios and the forced-oscillation technique, respectively. Bronchoalveolar lavage fluid cytokines and chemokines were measured by ELISA.Results.?Relative to WT mice, influenza-infected HETs showed significantly delayed mortality, which was accompanied by attenuated hypoxemia, cardiopulmonary dysfunction, and pulmonary edema. However, viral replication and weight loss did not differ. The protective HET phenotype was correlated with exaggerated alveolar macrophage and IL-6 response to infection and was abrogated by alveolar macrophage depletion using clodronate liposomes.Conclusions.?Reduced CFTR expression modulates the innate immune response to influenza and alters disease pathogenesis. CFTR-mediated Cl^- secretion is therefore an important host determinant of disease and CFTR inhibition may be of therapeutic benefit in influenza.