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G ranulocyte-macrophage colony-stimulating factor (GM-CSF) gene-targeted mice (GM^–/–) cleared group B streptococcus (GBS) from the lungs more slowly than wild-type mice. Expression of GM-CSF in the respiratory epithelium of GM^–/– mice improved bacterial clearance to levels greater than that in wild-type GM^+/+ mice. Acute aerosolization of GM-CSF to GM^+/+ mice significantly enhanced clearance of GBS at 24 hours. GBS infection was associated with increased neutrophilic infiltration in lungs of GM^–/– mice, while macrophage infiltrates predominated in wild-type mice, suggesting an abnormality in macrophage clearance of bacteria in the absence of GM-CSF. While phagocytosis of GBS was unaltered, production of superoxide radicals and hydrogen peroxide was markedly deficient in macrophages from GM^–/– mice. Lipid peroxidation, assessed by measuring the isoprostane 8-iso-PGF_2α, was decreased in the lungs of GM^–/– mice. GM-CSF plays an important role in GBS clearance in vivo, mediated in part by its role in enhancing superoxide and hydrogen peroxide production and bacterial killing by alveolar macrophages.