Acute respiratory distress syndrome (ARDS) is characterized by pulmonary vascular injury and altered endothelial permeability. Since Factor VIII antigen (VIII:Ag) is synthesized by endothelial cells, we studied FVIII:Ag and coagulant (VIII:C) activities in 100 patients with ARDS. Factor VIII:C was determined by one-stage assay, FVIII:Ag by quantitative immunoelectrophoresis and FVIII complexes by cross-immunoelectrophoresis (CIE). We studied 56 patients with mild acute lung injury (lobar infiltrate, mortality 30%), 30 with moderate ARDS (mortality 60%), and 14 with severe ARDS (mortality 90%) secondary to various etiologic agents. The results are expressed in % (Mean±SEM) as shown below: In all ARDS groups, there was a marked increase in FVIII: Ag by 4- to 5-fold the normal average. By CIE, both slow- and fast-moving components of FVIII:Ag displayed abnormal patterns. In moderate and severe ARDS, there was an increase in the fast-moving component of FVIII:Ag, mimicking vonWillebrand’s defect; this FVIII change may result in hemorrhage in the lung and elsewhere. In contrast, in mild ARDS there was an increase in FVIII:Ag slow-moving component which may account in part for the increase in pulmonary micro and/or macrothrombi formation. Recovery from ARDS resulted in return towards normal of FVIII:Ag patterns. Thus, FVIII:Ag appears to be a sensitive indicator of pulmonary endothelial injury and repair. In addition, our data strongly suggests that excessive concentrations and altered FVIII:Ag patterns may contribute to the thrombo- hemorrhagic complications commonly seen in acute lung injury.