Caloric restriction (CR) extends life span of healthy rodents compared to those fed ad libitum. Previous studies have shown positive effects of CR on the immune response of aged mice after influenza immunization. To extend these studies, a mouse model of CR was used to determine if CR could modulate primary responses of aged mice to influenza. Although CR delayed the age-related decrease in mitogen-induced lymphoproliferation of aged mice, in stark contrast, CR decreased survival, increased virus titers, and reduced natural killer cell activity in lungs of aged mice after primary influenza infection. Thus, CR has differential effects on immunity of aged mice, as general indices of immune response are maintained, but primary responses to influenza infection are impaired. This suggests that, although CR may positively affect many long-term parameters of aging, increased susceptibility after primary exposure of aged mice to virus, such as influenza, may not be correctable by CR.