Influenza infections cause airway epithelial inflammation and oxidant-mediated damage. In this setting, cellular antioxidant enzymes may protect airway epithelial cells against damage resulting from toxic oxygen radicals produced by activated leukocytes. Therefore, we tested the effect of influenza virus infection, as well as exposed to human recombinant interferon-gamma (IFN-gamma), on gene expression for the antioxidant enzymes manganese superoxide dismutase (MnSOD), copper/zinc superoxide dismutase (Cu/ZnSOD), indoleamine 2,3-dioxygenase (IDO), and catalase in primary cultures of human airway epithelial cells. In these cells, both viral infection and IFN-gamma increased MnSOD and IDO mRNAs. In contrast, neither viral infection nor IFN-gamma affected Cu/ZnSOD gene expression, and both viral infection and IFN-gamma decreased catalase gene expression. The differential effects of viral infection on antioxidant gene expression and their further amplification by IFN-gamma are likely to be important protective mechanisms in viral airway infections.