This study evaluated the pulmonary pathophysiology of the transgenic CFTR "gut-corrected" cystic fibrosis (CF) pigs. Four sows produced 18 piglets of which 11 were stillborn with only 2 animals surviving beyond 2 weeks. Failure to survive beyond the neonatal period by 5 piglets was judged to result from metabolic dysfunction related to genetic manipulation for CFTR gut expression or due to cloning artifact. Plasma analysis showed very low plasma proteins, highly elevated liver enzymes, and severe acidosis. All surviving offspring received furosemide for systemic edema. Physiologic evaluation was performed with lung tissues from the two surviving pigs. Both acetylcholine and forskolin induced mucous liquid secretion that was significantly lower in CF bronchi than non-CF bronchi. The percent non-volatile solids in mucus secreted from CF bronchi was elevated following acetylcholine or forskolin. Mucociliary transport in excised tracheas was reduced in the CF tracheas relative to nonCF tracheas. The diameter of CF tracheas was less than that of non-CF pigs in spite of their greater body weight. Despite exhibiting severe metabolic dysfunction during the neonatal period, this CF animal model appears to express important characteristics of human CF pulmonary disease.