In eight patients with Legg-Perthes disease, we assessed the etiologic roles of thrombophilia caused by protein C and protein S deficiency and hypofibrinolysis mediated by low levels of tissue plasminogen activator activity. We speculated that thrombosis or hypofibrinolysis were common causes of Legg-Perthes disease. Three of the eight patients had protein C deficiency; they came from kindreds with previously undiagnosed protein C deficiency. In one of these three kindreds there were six protein C-deficient family members (beyond the proband child), four of whom had thrombotic events as adults. One of the eight patients had protein S deficiency, as did his brother who had sustained mesenteric vein thrombosis at age 43. One of the eight patients who had normal proteins C, S, and antithrombin III had hypofibrinolysis, failing to elevate tissue plasminogen activator activity after 10 min of venous occlusion at 100 mm Hg. Plasminogen activator inhibitor, alpha 2-antiplasmin, and fibrinogen values were normal in all eight patients. Beyond their Legg-Perthes disease, none of the eight patients had evidence for venous thrombosis. Of the eight patients, four had thrombophilia and one had hypofibrinolysis, disorders that we believe contributed to thrombotic venous occlusion of the femur with subsequent venous hypertension and bone death that characterize Legg-Perthes disease.