Exhaled nitric oxide (FE) is a well-known, non-invasive airway biomarker. In patients with Cystic Fibrosis (CF) FE is decreased. To understand if reduced FE is primary related to Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) dysfunction or an epiphenomenon of chronic inflammation, we measured FE in 34 infants with CF prior to clinical symptoms and in 68 healthy controls. FE 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 is reduced in CF early in life, possibly associated with underlying CFTR dysfunction.