We have developed a model of gene therapy for cystic fibrosis (CF) lung disease, based on growth of human CF bronchial xenografts in nu/nu mice. We now report an evaluation of the primary abnormalities in CF lung epithelia--defective Cl secretion and Na hyperabsorption--in xenografts following adenovirus-mediated gene transfer. In vivo infection of CF xenografts with a cystic fibrosis transmembrane regulator (CFTR) recombinant adenovirus, at a multiplicity of infection equal to 100, was sufficient to reconstitute near normal levels of cAMP-stimulated Cl transport, despite transducing only 5% of cells in the pseudostratified epithelium. Correction in sodium hyperabsorption was partial and variable. These experiments define aspects of adenovirus-mediated gene therapy relevant to CF protocols based on intrapulmonary genetic reconstitution.