Introduction: The cystic fibrosis transmembrane conductance regulator (CFTR) chloride (Cl−) channel is an essential component of epithelial Cl− transport systems in many organs. CFTR is mainly expressed in the lung and other tissues, such as testis, duodenum, trachea and kidney. The ubiquitin ligase neural precursor cells expressed developmentally down-regulated protein 4-2 (Nedd4-2) has previously been shown to regulate abundance of several channel and carrier proteins in the plasma membrane, an effect reversed by glucocorticoid dependent kinase 1 (SGK1). Methods: The present study was thus performed to elucidate the sensitivity of CFTR to regulation by Nedd4-2 and the serum and SGK1. To this end, the CFTR was heterologously expressed in oocytes alone or together with Nedd4-2 or the SGK1. The cRNAs encoding CFTR, Nedd4-2 and/or the constitutively active S422DSGK1 have been injected into Xenopus oocytes. The activity of CFTR was measured by the two-electrode voltage-clamp technique and CFTR-mediated currents were elicited by the application of forskolin and IBMX (F/I). Results: As a result, forskolin/IBMX treatment triggered cAMP-stimulated ion currents (IcAMP) in Xenopus oocytes expressing CFTR cRNA, but not in oocytes injected with water (control). Co-expression of Nedd4-2 markedly down-regulates the cAMP-stimulated ion current (IcAMP), an effect reversed by Co-expression of the constitutively active S422DSGK1. In Xenopus oocytes co-expressing CFTR with S422DSGK1 the cAMP-stimulated ion current (IcAMP) was similar to that in Xenopus oocytes expressing CFTR alone. Conclusion: The present observations suggest that CFTR is a target for the ubiquitin ligase Nedd4-2, which is inactivated by the SGK1.