Neonates are highly susceptible to infectious diseases and, in general, respond poorly to conventional vaccines due to immaturity of the immune system. In the present study, we hypothesized that the anti-tetanus toxoid (TT) vaccine response of neonatal mice could be enhanced by retinoic acid (RA), a bioactive retinoid, and polyriboinosinic:polyribocytidylic acid (PIC), an inducer of IFN. Early-life treatments with RA and/or PIC were well tolerated and stimulated both primary anti-TT IgG production in infancy and the memory response in adulthood. TT-specific lymphocyte proliferation and type 1/type 2 cytokine production were also significantly augmented. In addition, RA and PIC modulated the maturation and/or differentiation of neonatal B cells, natural killer (NK)/NKT cells, and antigen-presenting cells. Although RA alone increased the neonatal anti-TT antibody response, it selectively increased anti-TT IgG1 and IL-5, resulting in a skewed type 2 response. PIC, a potent adjuvant in adult mice, elevated neonatal anti-TT IgG as well as all IgG isotypes (IgG1, IgG2a, and IgG2b) and induced TT-specific IFN-gamma, an important type 1 cytokine; however, PIC alone failed to benefit the memory response. The combination of RA plus PIC was more potent than either agent alone in elevating primary and secondary anti-TT IgG responses as well as IgG isotypes. Moreover, RA plus PIC increased TT-specific IFN-gamma and IL-5, suggesting the combination effectively promoted both type 1 and type 2 responses in neonatal mice. Thus, RA combined with PIC, a nutritional-immunological intervention, seems promising as an adjuvant for early-life vaccination.