Previous studies have suggested that the susceptibility of newborns to infections is linked to the immaturity of their immune system, but very few data are available on the early stages of maturation of the immune response. Therefore, we decided to investigate the evolution of the interferon (IFN)-α and interleukin (IL)-10 responses in neonatal mononuclear cells. To this end, mononuclear cells isolated from cord blood and peripheral blood of 2-, 6- and 18-month-old children and adults were stimulated with unmethylated cytosine-phosphate-guanosine oligodeoxynucleotide (CpG-ODN) 2216 (IFN-α response) or lipopolysaccharide (LPS) (IL-10 response) for 24 h. The production of IFN-α and IL-10 was then measured in culture supernatants using enzyme-linked immunosorbent assay (ELISA) or a 6-plex cytokine array, respectively. Compared to adults, we found a significant impairment in both the IFN-α and IL-10 responses of neonatal mononuclear cells. Interestingly, both responses had increased significantly after 2 months, but remained lower than the adult responses throughout the first 18 months of life. This study shows that although the immune response of neonates tends to mature fairly quickly, it remains different when compared to the adult immune response throughout the first 18 months of life. This could have important consequences on children's ability to mount an appropriate immune response to various challenges and to establish tolerance and immune homeostasis.