Cystic fibrosis patients exhibit chronic P. aeruginosa respiratory infections and sustained pro-inflammatory state favoring lung tissue damage and remodeling, ultimately leading to respiratory failure. Loss of CFTR function is associated with MAPK hyper-activation and increased cytokines expression, such as the interleukin 8 (CXCL8). Recently, new therapeutic strategies directly targeting the basic CFTR defect have been developed and ORKAMBI (Vx-809/Vx-770 combination) is the only FDA-approved treatment for CF patients homozygous for the F508del mutation. Here we aimed to determine the effect of the Vx-809/Vx-770 combination on the induction of the inflammatory response by fully-differentiated primary bronchial epithelial cell cultures from CF patients carrying F508del mutations, following exposure to P. aeruginosa exoproducts. Our data unveiled that CFTR functional rescue with Vx-809/Vx-770 drastically reduces CXCL8 (as well as CXCL1 and CXCL2) transcripts and p38 MAPK phosphorylation in response to P. aeruginosa exposure through a CFTR-dependent mechanism. These results suggest that ORKAMBI has anti-inflammatory properties that could decrease lung inflammation and contribute to the observed beneficial impact of this treatment in CF patients.