The influx of inflammatory mediators and cells into the tracheobronchial effluent of preterm infants with respiratory distress syndrome (RDS) appears to be important in signaling the development of bronchopulmonary dysplasia (BPD). The mechanism that initiates this early inflammatory response is not well understood. The purpose of this study was to test the hypothesis whether increased interleukin-8 (IL-8), a potent chemoattractant for human neutrophils, appears in the airways of preterm infants with RDS in whom BPD develops before the influx of neutrophils. In addition, airway secretions were analyzed for the cytokine interleukin-6 (IL-6) to test the hypothesis whether this pro-inflammatory cytokine is an early marker of inflammation in preterm infants with RDS who progress to BPD. Sixty-five infants less than 32 weeks gestation with RDS were enrolled on the first day of life and 56 infants completed the study, with 31 recovering from RDS (Non-BPD) and 25 infants progressing to BPD. Infants were excluded from enrollment in the presence of maternal chorioamnionitis, infection at birth, or infection within the first week of life. There were no significant differences in birthweight, gestational age, or prolonged rupture of membranes between the two groups. Serial tracheal aspirates (TA) were collected on days 1, 3, 5, and 7 while the infants remained intubated. Significant elevations of TA neutrophil counts were detected in the BPD group on days 5 and 7. Cell-free TA revealed marked elevations of IL-8 in the BPD group compared to the Non-BPD group [median (25th percentile, 75th percentile), ng/ml epithelial lining fluid (ELF)] on day 1 [BPD 485 (195, 840); Non-BPD 63.1 (28.3, 197), P < 0.05] and day 3 [BPD 740 (319, 1310); Non-BPD 111 (54.3, 337); P < 0.05], while on days 5 and 7, the differences were not statistically significant. Interleukin-6 (IL-6) was measured as a marker of acute inflammation and was not different in the two groups on day 1, but was significantly elevated on day 3 [median (25th percentile, 75th percentile), ng/ml ELF; BPD 297 (62.1, 702); Non-BPD 72 (32.8, 266), P < 0.05] and on day 5 [BPD 270 (136, 672); Non-BPD 86.4 (57.8, 138), P < 0.05]. These studies demonstrate that elevation of IL-8 and IL-6 levels precedes the marked neutrophil influx seen in the TA of preterm infants in whom BPD develop. The presence of IL-8 and IL-6 in TA from these infants suggests that these cytokines either initiate the acute inflammatory cascade in the lungs, or they are early markers of the inflammatory process that places preterm infants at high risk for BPD.