Inhalation injury is one of the main causes of mortality in burn victims. The tracheobronchial epithelium sloughs and combines with a protein rich exudate to form casts of the airways that can lead to obstruction. We studied the effects of a continuous infusion of heparin on the acute pulmonary injury that occurs after smoke inhalation injury in sheep. Twelve ewes with vascular catheters received a standardized smoke inhalation injury and mechanical ventilation according to protocol for 72 hours. The heparin group (n = 6) received a 400 unit per kilogram bolus of heparin followed by a continuous infusion to maintain the activated clotting time between 250 to 300 seconds. The control group (n = 6) received a saline solution vehicle. Hemodynamics, blood gases and plasma samples for conjugated dienes were taken every six hours. At necropsy, pulmonary tissue was collected for histologic findings, polymorphonuclear neutrophil leukosequestration, wet-to-dry weight ratios and conjugated dienes. PaO2 to FIO2 ratios were improved in the heparin group compared with the control group at 12 to 72 hours after injury, and peak airway pressures were higher in the control group compared with the heparin group. Positive end expiratory pressure requirements were higher in the control group compared with the heparin group. There were significantly fewer airway tracheobronchial casts as determined by our tracheobronchial casts scoring system (2.4 +/- 0.4 versus 0.67 +/- 0.21) and confirmed by histologic examination. Pulmonary blood-free wet-to-dry weight ratios were higher in the control group compared with the heparin group (6.4 +/- 0.5 versus 5.2 +/- 0.1; p < 0.05). There were no differences in pulmonary tissue or plasma conjugated dienes; likewise, pulmonary leukosequestration was unaffected by heparin. Heparin decreases tracheobronchial cast formation, improves oxygenation, minimizes barotrauma and reduces pulmonary edema in an ovine model of severe smoke inhalation injury. Heparin does not reduce oxygen free radical activity after smoke inhalation injury.