Three influenza virus pandemics occurred in the last century, in 1918 killing 40-50 million people. In the absence of strain-specific vaccines, with potential resistance to antivirals and the threat of an imminent pandemic, strategies that alleviate symptoms are a priority. Reactive oxygen species are potent antimicrobial agents but cause immunopathology when produced in excess. Mice lacking a functional phagocyte NADPH oxidase (Cybb tm1 mice) or treated with the metalloporphyrin antioxidant manganese (III) tetrakis (N-ethyl pyridinium-2-yl) porpyhrin (MnTE-2-PyP) show heightened inflammatory infiltrates in their airways in response to pulmonary influenza infection, with augmented macrophage populations and a Th1-skewed T cell infiltrate. Underlying this exuberant macrophage response was a significant reduction in apoptosis and down-regulation of the myeloid inhibitory molecule CD200. Both, Cybb tm1 and MnTE-2-PyP-treated mice exhibited a reduced influenza titer in the lung parenchyma. Inflammatory infiltrate into the lung parenchyma was markedly reduced and lung function significantly improved. Manipulation of the homeostatic control of myeloid cells by inflammatory mediators therefore represents a novel therapeutic strategy in the treatment of influenza virus infection.