Acute lung injury(ALI)is a major cause of morbidity and mortality in critically ill patients. Hyperoxia causes lung injury in animals and human, and is an established model of ALI. Caveolin-1, a major constituent of caveolae, regulates numerous biological processes including cell death and proliferation. Here we demonstrate that caveolin-1 null mice(cav-1^-/-)were resistant to hyperoxia-induced death and lung injury. Cav-1^-/- mice sustained reduced lung injury after hyperoxia as determined by protein levels in bronchoalveolar lavage fluid and histological analysis. Furthermore cav-1^-/- fibroblasts and endothelial cells and cav-1 knockdown epithelial cells resisted hyperoxia-induced cell death in vitro. Basal and inducible expression of the stress protein heme oxygenase-1 (HO-1) were markedly elevated in lung tissue or fibroblasts from cav-1^-/- mice. Hyperoxia induced the physical interaction between cav-1 and HO-1 in fibroblasts assessed by co-immunoprecipitation,studies, which resulted in attenuation of HO activity. Inhibition of HO activity with tin protoporphyrin-IX, abolished the survival benefits of cav-1^-/- cells and cav-1^-/- mice exposed to hyperoxia. The cav-1^-/- mice displayed elevated phospho-p38 MAPK and p38 expression in lung tissue /cells under basal conditions and during hyperoxia. Treatment with SB202190, an inhibitor of p38 MAPK, decreased hyperoxia-inducible HO-1 expression in wild-type and cav-1^-/- fibroblasts. Taken together, our data demonstrated that cav-1 deletion protects against hyperoxia-induced lung injury, involving in part via the modulation of the HO-1/cav-1 interaction, and the enhanced induction of HO-1 through a p38 MAPK-mediated pathway. These studies identify caveolin-1 as a novel component involved in hyperoxia induced lung injury.