The mechanisms underlying the initiation of lung disease and early respiratory morbidity in cystic fibrosis (CF) are poorly understood. By identifying infants with CF through a statewide neonatal screening program, we investigated whether airway inflammation was present in these infants, with the goal of furthering our understanding of the early events in this lung disease. Bronchoalveolar lavage fluid (BALF) from 16 infants with CF (mean age, 6 mo) and 11 disease control infants (mean age, 12 mo) was examined for the following inflammatory parameters: (1) neutrophil count; (2) activity of free neutrophil elastase; (3) elastase/alpha 1-antiprotease inhibitor complexes; and (4) the level of interleukin-8 (IL-8). We also quantified the spontaneous level of expression of IL-8 mRNA transcripts by airway macrophages. Each index of airway inflammation was increased in the BALF of infants with CF as compared with control infants. In addition, both the number of neutrophils and IL-8 levels were increased in infants with CF who had negative cultures (n = 7) for common bacterial CF-related pathogens, as well as for common respiratory viruses and fungi at the time of bronchoalveolar lavage (BAL). These findings suggest that airway inflammation is already present in infants with CF who are as young as 4 wks. Furthermore, although many different cell types (e.g., epithelial cells) may express IL-8, airway macrophages appear to be a source of this chemokine, and may thus play a prominent role in early neutrophil influx into the lung.