Ozone is a ubiquitous air pollutant that can cause acute pulmonary inflammation and cell injury and may contribute to the exacerbation of chronic pulmonary diseases. The molecular mechanisms of ozone-induced cell injury, as well as protective mechanisms against ozone-injury, are not well understood. Since ozone is a reactive oxidant, and heme oxygenase-1 (HO-1) is an antioxidant enzyme induced by many oxidative stimuli, we hypothesized that HO-1 is one of the protective mechanisms against ozone-induced cell injury, as well as pulmonary inflammation. In the current study, C57BI/6 mice were pretreated with a low level of endotoxin (lipopolysaccharide, LPS) (0.5 mg/kg) to induce HO-1, and 16 h later were exposed to 1 ppm ozone for 3 h. Endotoxin pretreatment caused a significant protection against ozone-induced pulmonary inflammation and cell injury in bronchoalveolar lavage (BAL) cells. The protection by endotoxin pretreatment against ozone-induced inflammation and necrosis in BAL cells was abolished by the cotreatment with a heme oxygenase inhibitor, tin protoporphyrin IX dichloride (SnPP), suggesting that HO-1 is responsible for the protection against ozone-induced pulmonary inflammation and BAL cell necrosis. Therefore, since HO-1 is induced following ozone exposure, HO-1 may contribute to the development of cellular adaptation to chronic ozone exposure.