Background Long-term benefits of newborn screening (NBS) for cystic fibrosis (CF) have been established with respect to nutritional status, but effects on pulmonary health remain unclear. Hypothesis With early diagnosis and commencement of standardised treatment, lung function at w3 months of age is normal in NBS infants with CF. Methods Lung clearance index (LCI) and functional residual capacity (FRC) using multiple breath washout (MBW), plethysmographic (pleth) FRC and forced expirations from raised lung volumes were measured in 71 infants with CF (participants in the London CF Collaboration) and 54 contemporaneous healthy controls age w3 months. Results Compared with controls, and after adjustment for body size and age, LCI, FRC MBW and FRC pleth were significantly higher in infants with CF (mean difference (95% CI): 0.5 (0.1 to 0.9), p¼0.02; 0.4 (0.1 to 0.7), p¼0.02 and 0.9 (0.4 to 1.3), p<0.001, z-scores, respectively), while forced expiratory volume (FEV 0.5 ) and flows (FEF 25e75 ) were significantly lower (À0.9 (À1.3 to À0.6), p<0.001 and À0.7 (À1.1 to À0.2), p¼0.004, z-scores, respectively). 21% (15/70) of infants with CF had an elevated LCI (>1.96 z-scores) and 25% (17/68) an abnormally low FEV 0.5 (below À1.96 z-scores). While only eight infants with CF had abnormalities of LCI and FEV 0.5 , using both techniques identified abnormalities in 35% (24/68). Hyperinflation (FRC pleth >1.96 z-scores) was identified in 18% (10/56) of infants with CF and was significantly correlated with diminished FEF 25e75 (r¼À0.43, p<0.001) but not with LCI or FEV 0.5 . Conclusion Despite early diagnosis of CF by NBS and protocol-driven treatment in specialist centres, abnormal lung function, with increased ventilation inhomogeneity and hyperinflation and diminished airway function, is evident in many infants with CF diagnosed through NBS by 3 months of age.