Implementation of a CF neonatal screening program in Belgium could help avoid a potentially long, painful, and costly diagnostic odyssey and will improve height and weight gain in children diagnosed early. CF NBS could also benefit pulmonary status and reduce the therapy burden, but this is not based on RCT data. The beneficial effects on survival may have become undetectable given the improvement in care. The benefits of CF NBS override potential harms only if several quality criteria for screening are strictly followed. The budget impact of implementing CF NBS is small compared to the annual budget expenditures to reimburse CF DNA tests.