Background: Although intrapulmonary fibrin deposition is a pathognomonic feature of acute lung injury, it remains uncertain whether treatment with different thrombin inhibitors improves clinically important outcomes. Objective: To study the effects of heparin and/or antithrombin concentrate on gas exchange in newborn piglets with experimental neonatal respiratory distress syndrome. Methods: 48 piglets were randomized within 12 litters to 1 of 4 treatment groups: 1. Antithrombin (250 U/kg loading dose i.v followed by 100 U/kg every 6 h); 2. Heparin (50 U/kg loading dose i.v. followed by 30 U/kg/h); 3. Antithrombin plus heparin; 4. No anticoagulant therapy. All piglets received standardized lung lavage and 4 hours of high-pressure ventilation to create lung injury. Mechanical ventilation was continued for 24 hours during which ventilator pressures and inspired oxygen were adjusted to maintain normal arterial blood gases. All animals were paralyzed and sedated during the entire experiment. The arterial/alveolar oxygen tension ratio (a/A ratio) and the ventilator efficiency index (VEI) were calculated at 18 and 24 hours and compared by repeated measures anova. Other outcome measurements included the accumulation in lung parenchyma of intravenously administered 125-I-fibrinogen and lung histology scores. A pathologist who was unaware of group allocations performed the histological examination using the scoring system by Tsuno et al (Am Rev Respir Dis 143:1115, 1991). Results: Both oxygenation and ventilation indices were improved in piglets receiving heparin compared to those receiving no treatment or antithrombin concentrate without heparin: Mean(SD) a/A ratio 0.48 (0.27) versus 0.33 (0.26); p=0.01. Mean (SD) VEI 0.30(0.12) versus 0.25 (0.14); p=0.043. There was also a trend towards reduced lung deposition of 125-I-fibrinogen (p=0.08) and improved histology scores(p=0.09) in heparin-treated animals. Conclusion: A continuous infusion of heparin improved gas exchange during experimental acute lung injury in newborn piglets.Funded by the Medical Research Council of Canada