There is strong evidence that abnormal airway ion transport is the primary defect that initiates the pathophysiology of lung disease in cystic fibrosis (CF). To examine the relationship between airway ion transport abnormality and severity of lung disease, we measured nasal potential difference in 51 young people with CF using a validated modified technique. There was no correlation between any component of the ion transport measurement and clinical condition (respiratory function, chest radiograph score, or Shwachman clinical score). Thirty subjects, homozygous for the DeltaF508 mutation, were divided into those above and those below average respiratory function for their age. There was no significant difference in any of the ion transport parameters between those with above and below average pulmonary function. Of the 51 subjects, 10 had significant hyperpolarization after perfusion with a zero Cl- solution (> 5 mV). This Cl- secretory capacity did not correlate with above average lung function. These data do not support the assertion that the extent of lung disease in CF reflects the degree of ion transport abnormality. We suggest that although an ion transport abnormality initiates lung disease, other factors (e.g., environmental and genetic modifiers) are more influential in determining disease severity.