Smoke inhalation increases mortality and morbidity in burn patients. We have reported that smoke inhalation increases lung lymph flow, an index of pulmonary transvascular fluid flux and decreases reflection coefficient, an index of microvascular permeability to protein. Nitric oxide has been reported to decrease microvascular permeability to protein. We hypothesize that inhaled nitric oxide decreases pulmonary microvascular hyperpermeability following smoke inhalation. Sheep were prepared for study with a chronic lung lymph fistula, Swan-Ganz, left atrial, and femoral arterial catheters. Occluders were placed on pulmonary veins to measure reflection coefficient. All animals were insufflated with 4 x 12 breaths of cotton smoke. Sheep were randomly divided into two groups: NO (injured, treated with nitric oxide (40 ppm) inhalation, n=6) and control (injured, not treated, n=6). Nitric oxide inhalation was started 22 h after the insult. Control animals showed an increase in lung lymph flow, and lung water content. These changes were associated with marked increase in pulmonary microvascular resistance, pulmonary artery pressure, and decrease in reflection coefficient. Nitric oxide inhalation ameliorated the above-mentioned pathological changes. The results suggest that nitric oxide inhalation has potential for beneficial effect in the treatment of patients suffering from smoke inhalation.