Genotype-phenotype analyses in cystic fibrosis (CF) have shown that cystic fibrosis transmembrane conductance regulator (CFTR) genotypes can predict pancreatic status but that correlations with pulmonary status remain elusive. We investigated the extent and severity of lung disease associated with CFTR mutation S549R (T-->G). This mutation is localized in intron 11 (nucleotide-binding fold 1 of the CFTR protein) and had so far been described as a private mutation only. It is associated with an extremely severe overall CF phenotypic expression. Detailed radiological analyses were performed by a single observer in 12 children with CF from the United Arab Emirates who were homozygous for CFTR mutation S549R (T-->G). A diversity of pulmonary changes included marked hyperinflation in early infancy in conjunction with inflammation of the interstitium. After 2 years of age, signs of central airway involvement occurred in association with early signs of pulmonary hypertension. In conclusion, although there is some diversity in the radiological findings of these CF patients, R549 is a very severe allele associated with extreme lung disease and rapid pulmonary decline.