Early negative life events, especially during the neonatal period, resulted in long lasting, irreversible effects on well being. The goal of the following study was to examine the lifelong effects of neonatal stress on the response to an influenza viral infection. Mouse pups were repeatedly separated from their dams between postnatal days 1-14 (maternal separation, MSP). As adults, these mice were infected with influenza A/PR8 virus and lung cytokine and plasma corticosterone responses to the viral infection were measured. The results indicated that MSP augmented several aspects of the response to infection. First, infection-induced lung proinflammatory cytokine (interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-alpha) mRNA expression was higher in MSP mice compared to controls. In addition, MSP augmented infection-induced lung IL-12 and interferon (IFN)-gamma, but had no effect on IL-18 mRNA. Interestingly, MSP-induced increase in IL-1, TNF-alpha and IFN-gamma mRNA expression was evident in females, but not in males. These findings suggest that MSP disrupted the regulation of innate resistance resulting in enhanced cytokine responses in the lungs during an infectious challenge. These changes in host response to the viral infection were accompanied by an increase in viral replication in lungs of MSP mice. Interestingly, influenza-induced corticosterone secretion was blunted in MSP mice, suggesting that the increase in immune reactivity to the virus was due to lack of glucocorticoid feedback control. These data demonstrate that neonatal stress has implications for host resistance to infection throughout life. Thus, long lasting effects of negative life events on health and disease may be the basis for the individual differences in host susceptibility to infection.