Here we investigated whether hydrogen can protect the lung from chronic injury induced by hypoxia/re-oxygenation (H/R). We developed a mouse model in which H/R exposure triggered clinically typical lung injury, involving increased alveolar wall thickening, infiltration by neutrophils, consolidation, alveolar hemorrhage, increased levels of inflammatory factors and recruitment of M1 macrophages. All these processes were attenuated in the presence of H2. We found that H/R-induced injury in our mouse model was associated with production of hydroxyl radicals as well as increased levels of colony-stimulating factors and circulating leukocytes. H2 attenuated H/R-induced production of hydroxyl radicals, up-regulation of colony-stimulating factors, and recruitment of neutrophils and M1 macrophages to lung tissues. However, H2 did not substantially affect the H/R-induced increase in erythropoietin or pulmonary artery remodeling. Our results suggest that H2 ameliorates H/R-induced lung injury by inhibiting hydroxyl radical production and inflammation in lungs. It may also prevent colony-stimulating factors from mobilizing progenitors in response to H/R-induced injury.