Given the susceptibility of newborns to infection and the potential harm of overwhelming proinflammatory immune responses, the impact of genetic variation in innate immune molecules is of increasing interest for risk stratification and prevention. We studied the functional relevance of the 159C>T CD14 single nucleotide polymorphism in cord blood samples of n=135 healthy term neonates by investigation of sCD14, interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-alpha concentrations in whole-blood culture supernatants and intracellular assessment of IL-1beta, IL-6, and TNF-alpha expression by flow cytometry. The 159C>T CD14 genotype frequencies were n=42 (0.31) for homozygous CD14-159 CC, n=69 (0.51) for heterozygous CD14-159 CT, and n=24 (0.18) for homozygous CD14-159 TT. No genotype-associated differences were noted for ex vivo baseline expression of sCD14, IL-6, IL-10, and TNF-alpha. After in vitro stimulation of cord blood cultures with lipopolysaccharide, carriers of the CD14-159 T allele were determined to have higher levels of sCD14 compared with carriers of the CD14-159 C allele (p=0.04) and increased concentrations of IL-6 (p=0.009) in culture supernatants (one-way analysis of variance). The 159C>T CD14 polymorphism is associated with soluble CD14 expression and cytokine expression, which might influence the balance of pro- and anti-inflammatory immune responses in healthy term neonates. Further studies are needed to delineate whether the 159C>T CD14 genotype is a risk factor for severity of neonatal infection in the clinical setting and a potential target for prevention strategies.