Exhaled nitric oxide (FE _NO ) is a well-known, non-invasive airway biomarker. In patients with Cystic Fibrosis (CF) FE _NO is decreased. To understand if reduced FE _NO is primary related to Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) dysfunction or an epiphenomenon of chronic inflammation, we measured FE _NO in 34 infants with CF prior to clinical symptoms and in 68 healthy controls. FE _NO was lower in CF compared to controls (p=0.0006) and the effect was more pronounced in CF infants without residual CFTR function (p<0.0001). This suggests that FE _NO is reduced in CF early in life, possibly associated with underlying CFTR dysfunction.