IN cystic fibrosis (CF), numerous epithelial cell functions are abnormal, including Cl⁻ conductance, sodium absorption, mucin sulphation and enzyme secretion^1–4. Although the CF gene product, the cystic fibrosis transmembrane conductance regulator (CFTR), functions as a small linear Cl⁻ channel^5–8, it is difficult to attribute such pleiotropic disease manifestations solely to a defect in Cl⁻ conductance. This has led to speculation that CFTR regulates the activity of other proteins. One possible example is the protein kinase A activation of outward rectifying Cl⁻ channels (ORCC), which is defective in membrane patches excised from CF cells^9–16. Whether CFTR regulates the activity of an independent anion channel is debatable, because ORCC occur exclusively in excised membrane patches and could be an excision-induced molecular derivative of CFTR. 'Knockout' mice that lack CFTR^17,18 provide a means to define the relationship between CFTR and ORCC. Here we report that ORCC are present in CFTR(−/−) mouse nasal epithelial cells and thus cannot be a derivative of the CFTR molecule. Also ORCC were regulated by protein kinase A in membrane patches from normal but not CFTR(−/−) cells. These observations are the first, to our knowledge definitive demonstration that CFTR regulates the activity of another protein.