Energy restriction (ER) without malnutrition extends lifespan in mice and postpones age-related changes in immunity. However, we have previously shown that aged (22 mo old) ER mice exhibit increased mortality, impaired viral clearance, and reduced natural killer (NK) cell cytotoxicity following influenza infection compared with aged mice that consumed food ad libitum (AL). To determine whether the detrimental effects of ER in response to influenza infection occur independently of advanced age, young adult (6 mo) male C57BL/6 mice consuming an AL or ER diet were infected with influenza A virus (H1N1, PR8). Young adult ER mice exhibited increased mortality (P < 0.05) and weight loss (P < 0.01) in response to infection. ER mice exhibited decreased total (P < 0.001) and NK1.1+ lymphocytes (P < 0.05) in lung and reduced influenza-induced NK cell cytotoxicity in both lung (P < 0.01) and spleen (P < 0.05). Importantly, the mRNA expression of interferon (IFN)alpha/beta (P < 0.05) was also reduced in the lungs of ER mice in response to infection, and in vitro stimulation of NK cells from ER mice with type I IFN resulted in cytotoxicity comparable to that in NK cells from AL mice. In contrast, NK cell activation was enhanced in ER mice, determined as an increase in the percentage of NK cells expressing B220 (P < 0.001) and increased intracellular production of IFNgamma (P < 0.01). These data describe an age-independent and detrimental effect of ER on the innate immune response to influenza infection and suggest that a decrease in NK cell number and alterations in the NK cell-activating environment may contribute to decreased innate immunity in ER mice.