OBJECTIVE: To explore the expression and function of nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2 and provide guidance for prophylaxis and treatment of neonatal infection. METHODS: Peripheral blood samples were collected from preterm infants, term infants and, healthy adult volunteers. A portion of collected blood was used to examine the expression of NOD1 and NOD2 by real-time PCR. The remaining blood was stimulated in vitro with NOD2 agonist L-Ala-D-Glu-meso (Tri-DAP) or NOD1 agonist muramyl dipeptide (MurNAc-L-Ala-D-isoGln; MDP) for 4?h. Consequently, the levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) were quantified by enzyme-linked immunosorbent assay (ELISA). RESULTS: NOD1 expression was found to be decreased in preterm and term newborns compared with adults. NOD2 was significantly lower in preterm infants alone in comparison with adults. After treated by Tri-DAP or MDP, the levels of IL-6 and TNF-α in peripheral blood were significantly lower in preterm and term newborns when comparing to adults. CONCLUSION: NOD1 and NOD2 expression and induced release of pro-inflammatory mediators were impaired in infants, contributing to the high susceptibility of infants to infection. Our results insisted on developing a new immunological approach for prophylaxis and treatment of neonatal infection.