The genetic disease Cystic Fibrosis (CF) is caused by a defective cystic fibrosis transmembrane conductance regulator (CFTR) gene. The most common mutation DF508 impairs functional CFTR expression, due to trafficking defects of the protein. In the present study we investigated the effect and activation mechanism of the phosphodiesterase 5 blocker sildenafil (SL). To verify if SL acts via a cGMP dependent pathway we inhibited the guanyl cyclase as well as the proteinkinase G (PKG) by specific inhibitors. SL was injected into CFTR expressing Xenopus laevis oocytes and cAMP mediated current (I_m), conductance (G_m), and capacitance (C_m) were analysed. We measured increased I_m, G_m, and C_m in wt-CFTR oocytes, which could be inhibted by the specific PKG and guanyl cyclase blockers. Additionally, we detected a restored I_m, and G_m in DF508-CFTR expressing oocytes. Using human bronchial epithelial DF508-CFTR (CFBE41o^-) and wt-CFTR (16HBE14o^-) cells we confirmed the effects of SL. Ussing chamber experiments revealed an increase (wt-CFTR) and a restoration (DF508-CFTR) of the channel activity by SL. In Western blot and immunofluorescence approaches we showed that SL induced an insertion of CFTR molecules into the plasma membrane of 16HBE14o^- and CFBE41o^- cells. In these experiments both blockers were able to inhibit the activity increase but not the insertion of CFTR molecules by SL. These experiments indicate that SL acts as a corrector as well as a potentiator of CFTR function. Possibly, the potentiating effect is mediated via a cGMP dependent pathway, whereas the CFTR correction acts independently of cGMP.