The aim of this study was to assess the serum concentrations of Clara cell secretory protein (CC16) in association with acute and chronic lung injury in mechanically ventilated preterm neonates. Thirty-five preterm neonates (gestational age [GA] <or=31 weeks) with acute respiratory failure were enrolled. Of these, 23 neonates requiring ventilatory support within 2 h after birth comprised the mechanically ventilated group (MV group), and 12 neonates who were not ventilated made up the nonventilated group (NV group). Serum CC16 was measured (using enzyme-linked immunosorbent assay [ELISA]) within 2 h (T0) and at 72 h (T1) after birth, at day 14 of life (T2) and at 36 weeks postmenstrual age (T3). The median CC16 concentrations were significantly higher in the MV group compared to the NV group at all times. Analysis with respect to differences observed in the group characteristics showed that GA, Apgar score at 5 min and mechanical ventilation were significant covariates of serum CC16 at T0. All neonates in the NV group and 18 cases in the MV group, respectively, survived discharge. Ventilated survivors with later bronchopulmonary dysplasia (BPD; oxygen requirement at T3, n = 7) had significantly higher CC16 at all times compared to nonventilated neonates. Elevated serum CC16 levels at T2 were predictive of BPD development. In conclusion, our results show that serum CC16 increases significantly in preterm neonates ventilated early after birth and remains high in those with later BPD. Further research is needed to validate the usefulness of CC16 as a peripheral blood biomarker of acute and chronic lung injury.