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In 30 patients with osteonecrosis of the hip (12 idiopathic, 18 secondary), we assessed the role of hypofibrinolysis mediated by high levels of plasminogen activator inhibitor (PAI). We evaluated hypofibrinolysis as a common, potentially reversible, pathophysiologic cause of idiopathic osteonecrosis. In all 18 patients with secondary osteonecrosis, PAI was normal, as was the ability to activate fibrinolysis. Nine of the 12 patients with idiopathic osteonecrosis had exceptionally high PAI levels and could not normally elevate tissue plasminogen activator (tPA-Fx), the major stimulator of fibrinolysis, after 10 min of venous occlusion at 100 mm Hg. The group of 12 patients with idiopathic osteonecrosis, compared to the 18 with secondary osteonecrosis, had low mean stimulated tPA-Fx (1.92 vs. 7.6 IU/ml, P < or = .001) and very high stimulated PAI-Fx (70 vs. 7.6 U/ml, P < or = .01). Three of the 12 patients with idiopathic osteonecrosis had both normal PAI and normal stimulated tPA-Fx. These three patients and 14 of the 18 with secondary osteonecrosis had high lipoprotein (a) [Lp(a)] (> 20 mg/dl). Mean Lp(a) was much higher (60 mg/dl) in the patients with secondary osteonecrosis than Lp(a) (16 mg/dl, P < or = .001) in the 12 patients with idiopathic osteonecrosis. These findings suggest that hypofibrinolysis mediated by high PAI is a common cause of idiopathic osteonecrosis, whereas high Lp(a) may play an etiologic role in secondary osteonecrosis. Prospective studies of patients with high PAI and/or high Lp(a) should be carried out to assess further their apparently causal roles in osteonecrosis.