Airway epithelial cells bearing mutations of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) possess an increased Na⁺ conductance along with their well described defect of cAMP dependent Cl⁻ conductance. Currently it is not clear, how this occurs, and whether it is due to a CFTR control of epithelial Na⁺ conductances which might be defective in CF patients. In the present study, we have tried to identify possible interactions between both CFTR and the epithelial Na⁺ conductance by overexpressing respective cRNAs in Xenopus oocytes. The expression of all three (α, β, γ) subunits of the rat epithelial Na⁺ channel (rENaC) and wild type (wt) CFTR resulted in the expected amiloride sensitive Na⁺ and IBMX (1 mmol/l) activated Cl⁻ currents, respectively. The amiloride sensitive Na⁺ conductance was, however, inhibited when the wt‐CFTR Cl⁻ conductance was activated by phosphodiesterase inhibition (IBMX). In contrast, IBMX had no such effect in ΔF508 and Na⁺ channels coexpressing oocytes. These results suggest that wt‐CFTR, but not ΔF508‐CFTR, is a cAMP dependent downregulator of epithelial Na⁺ channels. This may explain the higher Na⁺ conductance observed in airway epithelial cells of CF patients.