This study was designed to determine the effects of vitamin C deficiency on the immune response to infection with influenza virus. L-Gulono-γ-lactone oxidase gene-inactivated mice (gulo−/− mice) require vitamin C supplementation for survival. Five-wk-old male and female gulo−/− mice were provided water or water containing 1.67 mmol/L vitamin C for 3 wk before inoculation with influenza A/Bangkok/1/79. There were no differences in lung influenza virus titers between vitamin C–adequate and –deficient mice; however, lung pathology in the vitamin C–deficient mice was greater at 1 and 3 d after infection but less at d 7 compared with vitamin C–adequate mice. Male vitamin C–deficient mice had higher expression of mRNA for regulated upon activation normal T expressed and secreted (RANTES), IL-1β, and TNF-α in the lungs at d 1 after infection compared with male controls. However, at d 3 after infection, male vitamin C–deficient mice had less expression of mRNA for RANTES, monocyte chemotactic protein-1 (MCP-1), and IL-12 compared with male controls. None of these differences were observed in female mice. Vitamin C–deficient male mice also had greater nuclear factor-κB activation as early as 1 d after infection compared with male controls. These data suggest that vitamin C is required for an adequate immune response in limiting lung pathology after influenza virus infection.