Chronic lung disease (CLD) in premature newborns is associated with increased concentrations of inflammatory cytokines in tracheal aspirates (TA). We determined if polymorphisms of cytokine genes influence the risk of developing CLD by genotyping 178 mechanically ventilated very low birth weight (VLBW) infants for the tumor necrosis factor-alpha (TNF-alpha) -308 G/A, transforming growth factor-beta(1) (TGF-beta(1)) +915 G/C and monocyte chemoattractant protein-1 (MCP-1) -2518 A/G polymorphisms. Genomic DNA was isolated from TA and genotypes determined by restriction length polymorphism. There was no effect of any of these polymorphisms on the development of CLD (29 vs 23%, P=0.371, TNF-alpha -308 AA/AG vs TNF-alpha -308 GG; 23 vs 26%, P=0.681, MCP-1 -2518 GG/AG vs MCP-1 -215-8 AA; 24 vs 24%, P=0.978, TGF-beta(1) +915 CG vs TGF-beta(1) +915 GG). TA IL-8 and MCP-1 concentrations were not different between genotype groups. Infants with the TNF-alpha -308 A allele had increased risk of IVH (RR 2.07; 95% CI 1.02-4.18, P=0.041) and infants with the TGF-beta(1) +915 C allele were at greater risk of death (32 vs 9%, P=0.016). These data suggest that these polymorphisms do not play a significant role in determining risk for CLD in preterm infants, but may play a role in other complications in the neonatal period.