Rationale: Human data suggest that the incidence of acute lung injury is reduced in patients with type II diabetes mellitus. However, the mechanisms by which diabetes confers protection from lung injury are unknown. Objectives: To determine whether leptin resistance, which is seen in diabetics, protects mice from hyperoxic lung injury. Methods: Wild-type (leptin responsive) and db/db (leptin resistant) mice were used in these studies. Mice were exposed to hyperoxia (100% O2) for 84 hours to induce lung injury and up to 168 hours for survival studies. Alveolar fluid clearance was measured in vivo. Measurements and Main Results: Lung leptin levels were increased both in wild-type and leptin receptor defective, db/db mice after hyperoxia. Hyperoxia-induced lung injury was decreased in db/db compared to wild-type mice. Hyperoxia increased lung permeability in wild-type mice but not in db/db mice. Compared to wild-type controls, db/db mice were resistant to hyperoxia-induced mortality (LD50 152 vs. 108 hours). Intratracheal instillation of leptin at a dose that was observed in the bronchoalveolar lavage fluid during hyperoxia caused lung injury in wild-type but not in db/db mice. Intratracheal pretreatment with a leptin receptor inhibitor attenuated leptin-induced lung edema. The hyperoxia-induced release of pro-inflammatory cytokines was attenuated in db/db mice. Despite resistance to lung injury, db/db mice had diminished alveolar fluid clearance and reduced Na,K-ATPase function compared to wild-type mice. Conclusions: These results indicate that leptin can induce and that resistance to leptin attenuates hyperoxia-induced lung injury and hyperoxia-induced inflammatory cytokines in the lung.