A number of studies have shown that increased numbers of neutrophils and macrophages are recruited into the airways during the development of chronic lung disease (CLD) in preterm infants. The objective of this study was to determine whether the anaphylatoxin C5a is detectable in tracheobronchial aspirate fluid of infants at risk for CLD and to evaluate the possible effects of dexamethasonc (Dxm) treatment. C5a/C5a(des Arg) levels were determined by a sensitive ELISA based on a neoepitope-specific MAb. In a prospective study, 27 infants (birth weight 881 ± 169 g, mean ± SD) still on mechanical ventilation at d 10 postnatal age with fraction of inspired oxygen ≥0.3 and/or peak inspiratory pressure ≥16 cm H2O were randomly assigned to Dxm treatment at d 10 (n = 14) or d 16 (n = 13). Ten mechanically ventilated infants with no respiratory disease or who had recovered from respiratory distress syndrome did not meet these criteria on d 10 and served as a control group (birth weight 928 ± 126 g). For the evaluation of Dxm therapy, the late treatment group was used as a control group for the early regimen. Compared with controls, C5a concentrations were higher in infants at risk for CLD on d 10 [median (25th-75th percentile): 2.40 (1.13–3.38) versus 0.82 (0.55–1.78) μg/L, p < 0.05]. After Dxm, C5a concentrations decreased significantly in the early treatment group compared with pretreatment values in the late treatment group [d 15, pre Dxm 2.22 (0.98–3.92), post Dxm 0.57 (0.18–1.02) μg/L, p < 0.01]. C5a levels in plasma of eight infants were not affected by Dxm treatment. Our results show that increased levels of complement anaphylatoxin C5a are present in lung effluent fluid of infants at risk for CLD, and that local but not systemic levels are affected by Dxm. These findings indicate a role of C5a in the recruitment of inflammatory cells into the airways of infants with CLD.