The morbidity and mortality of burn victims increase when combined with smoke inhalation. The goal of present study was to develop a murine model of burn and smoke inhalation injury to more precisely reveal the mechanistic aspects of these pathological changes. The burn injury mice group received a 40% total body surface area third-degree burn alone, the smoke inhalation injury mice group received two 30 sec exposures of cotton smoke alone, and the combined burn and smoke inhalation injury mice group received both the burn and the smoke inhalation injury. Animal survival was monitored for 120 hrs. Survival rates in the burn injury group, in the smoke inhalation injury group and in the combined injury group were 70%, 60% and 30%, respectively. Mice received combined burn and smoke injury developed greater lung damage as evidenced by histological changes (septal-thickening and interstitial edema) and higher lung water content. These mice also displayed more severely impaired pulmonary gas exchange (PaO2/FiO2 < 200). Lung myeloperoxidase activity was significantly higher in burn and smoke injured animals compared to the 3 experimental groups. Plasma NO2-/NO3-, lung iNOS activity and iNOS mRNA increased with injury; however, the burn and smoke injury group exhibited a higher response. Severity of burn and smoke inhalation injury was associated with more pronounced production of nitric oxide and accumulation of activated leukocytes in lung tissue. The murine model of burn and smoke inhalation injury allows us to better understand pathophysiological mechanisms underlying cardiopulmonary morbidity secondary to burn and smoke inhalation injury.