We determined whether antithrombin (AT III) or hirudin (a specific thrombin inhibitor) reduce both the accumulation of fibrinogen in lung parenchyma and the procoagulant activity of bronchoalveolar lavage (BAL) fluid during acute lung injury induced by pulmonary overdistention. Newborn piglets were randomized to six-hourly infusions of AT III concentrate, a continuous infusion of recombinant hirudin, or no anticoagulant therapy. All animals were subjected to 24 h of identical mechanical ventilation at high peak pressures (3.9 kPa or 40 cm H2O). Tidal volumes were raised to a mean of 69 mL/kg in all three groups. Mean AT III levels in supplemented piglets (n = 22) were increased to 1.46 (SD 0.24) U/mL at 24 h, compared with 0.67 (SD 0.16) U/mL in controls (n = 23). The median activated partial thromboplastin time in animals receiving hirudin (n = 18) was prolonged to 53 s versus 34 s in untreated animals. The intrapulmonary accumulation of i.v. administered 125I-fibrinogen was reduced by AT III concentrate or hirudin, compared with untreated littermates (p = 0.003). The procoagulant activity of BAL fluid was also decreased by both thrombin inhibitors (p = 0.001). Intrapulmonary accumulation of fibrinogen and the procoagulant activity of BAL fluid were reduced by AT III or hirudin during lung injury caused by pulmonary overdistention. Future investigations should determine whether tangible clinical benefits result from this reduced potential for fibrin deposition in the injured lung.