Cystic fibrosis (CF), due to mutations of the cystic fibrosis transmembrane conductance regulator (CFTR), exhibits a wide range of disease severity, even among &Dgr;F508 homozygous patients, and the mechanisms of this variability have yet to be elucidated. In view of the close structural homology and possible functional overlap between CFTR and Multidrug Resistance-associated Proteins (MRPs), MRPs were investigated as potentially relevant factors in CF pathophysiology.MRP1-5gene expression was analyzed in nasal respiratory epithelial cells from &Dgr;F508 homozygous patients (n= 19) and control subjects (n= 20) using semiquantitative RT-PCR. Significantly lowerMRP1andMRP5transcript levels were found in CF patients than in control subjects.MRP1andMRP5transcript levels were strongly correlated (r= 0.71). In CF patients, lowMRP1transcript levels were associated with more severe disease as assessed by the Shwachman score. A relation was also observed betweenMRP1levels and presence of a cAMP-independent chloride conductive pathway, as determined by a halide-sensitive fluorescent assay. These results suggest that MRPs, especially MRP1, might play a role in CF phenotype and might therefore constitute a target for a novel pharmacotherapy of CF.