OBJECTIVES: To determine whether the improved clinical status after newborn screening (NBS) for cystic fibrosis (CF) segregates with increased therapeutic intervention compared with presentation by clinical diagnosis (CD). STUDY DESIGN: In 2002, two populations (1 to 9 years of age) who presented (excluding meconium ileus) by NBS =3 months of age or by CD were compared in an observational, cross-sectional design. NBS and CD populations (184 and 950 patients, respectively) were divided into 3-year age groups (1 to 3, 4 to 6, and 7 to 9 years). Therapies of duration >3 months were compared together with Pseudomonas aeruginosa infection status. RESULTS: NBS patients =6 years of age received significantly fewer and less demanding therapies not explained by age, genotype, geography, or social deprivation. In 7- to 9-year-olds, significantly fewer NBS patients received intravenous antibiotics. NBS patients without P aeruginosa infection received significantly fewer therapies, but no differences were found between intermittently or chronically infected NBS and CD populations. Comparable results were found in ?F508/?F508 subpopulations. CONCLUSIONS: CF populations diagnosed by NBS are associated with reduced treatment compared with age- and genotype-matched CD control subjects.