Immunoreactive trypsinogen analysis applied to dried newborn specimens for recognition of cystic fibrosis risk was coupled with DNA-based detection of the Delta508 mutation during a combined period of 1985 to 1994. Randomization of 650,341 newborns resulted in two cohorts: an early diagnosis, screened cohort, and a standard diagnosis or control group. Anthropometric indexes of nutritional status including length/height, weight, and head circumference were significantly higher in the screened group despite a higher proportion of patients with pancreatic insufficiency in this cohort. Excluding infants presenting with meconium ileus, diagnosis was made at a much earlier age in screened patients. Incorporation of other infants with cystic fibrosis born during the randomization period resulted in a maximum calculated incidence of 1:3,398 (95% CI, 3,402 to 4,611). Early diagnosis facilitated by newborn screen appears to prevent the severe malnutrition that frequently accompanies delayed diagnosis.