It is not known at what age lung function impairment may arise in children with cystic fibrosis (CF). We assessed lung function shortly after birth in infants with CF diagnosed by newborn screening.We performed infant lung function measurements in a prospective cohort of infants with CF and healthy controls. We assessed lung clearance index (LCI), functional residual capacity (FRC) and tidal breathing parameters. The primary outcome was prevalence and severity of abnormal lung function (±1.64 z-scores) in CF.We enrolled 53 infants with CF (mean age 7.8 weeks) and 57 controls (mean age 5.2 weeks). Compared to controls, LCI and FRC were elevated (mean difference 0.30, 95% CI 0.02-0.60; p=0.034 and 14.5 mL, 95% CI 7.7-21.3 mL; p<0.001, respectively), while ratio of time to peak tidal expiratory flow to expiratory time was decreased in infants with CF. In 22 (41.5%) infants with CF, either LCI or FRC exceeded 1.64 z-scores; three infants had both elevated LCI and FRC.Shortly after birth, abnormal lung function is prevalent in CF infants. Ventilation inhomogeneity or hyperinflation may serve as noninvasive markers to monitor CF lung disease and specific treatment effects, and could thus be used as outcome parameters for future intervention studies in this age group.