IL-21, a member of the IL-2 cytokine family, is mainly produced by activated CD4(+) T cells and controls the activity of immune and also non-immune cells. As a pleiotropic cytokine, IL-21 acts on both innate and adaptive immune responses, suggesting that IL-21 may be a master regulator of the T-cell-dependent adaptive immune response. Although IL-21 is described as mostly promoting inflammation, evidence also suggests inhibitory effects of IL-21. However, its role, particularly in the human neonatal immune system, has not been detailed so far. Here, we assessed the effect of IL-21 in the specific context of the neonatal immune response and delineated differences between the human newborn and adult immune response. In umbilical cord blood, we demonstrated that IL-21 polarized naive CD4(+) T cells into T(h)1 cells, producing IL-10, a key negative regulator during certain infections and autoimmunity. Furthermore, IL-21 stimulation increased IFNγ secretion and inhibited the development of T(h)2 and T(h)17 cells and molecules associated with their function. Thus, in neonates, known to show limitations in establishing T(h)1 responses, IL-21 played a clear role in supporting T(h)1 responses in vitro, while appearing irrelevant for the adult immune response. Overall, we demonstrated the capability of IL-21 to induce the immunosuppressive cytokine IL-10 and outlined its potential to compensate the restricted T(h)1 response in human newborns and consequently to reduce the susceptibility for infectious diseases in the first period of life.