Acute respiratory failure is characterized by pulmonary vascular injury and increased endothelial permeability. Since endothelial cells synthesize or release factor VIII, we studied factor VIII:antigen, factor VIII:von Willebrand's factor, and factor VIII:coagulant activity in 100 patients with acute respiratory failure, in 29 critically ill patients without evidence of lung disease, and in 60 normal subjects. As a group, patients with respiratory failure had factor VIII:antigen levels that were five times normal, whereas their factor VIII:coagulant and von Willebrand's activities were normal or above normal. However, there was a remarkable disproportion between the levels of factor VIII:antigen and those of factor VIII:coagulant and von Willebrand's factor. In the other ill patients and in the normal group, these levels were in close proportion. In patients with respiratory failure, both slowly and rapidly migrating components of factor VIII:antigen had abnormal electrophoretic patterns; in moderate and severe cases, there was a marked increase in the fast component. Patients who recovered from acute respiratory failure had electrophoretic patterns that returned toward normal. Factor VIII:antigen may be a sensitive circulating indicator of pulmonary endothelial injury and repair.