Patients with essential thrombocythemia (ET) are at increased risk for large-vessel and microvascular thrombosis, presumably because of abnormal platelet number and function. To determine if another hemostatic abnormality might contribute to this thrombotic risk, we investigated protein C and protein S and the fibrinolytic system in four patients with ET. The patients segregated into two distinct groups. The first group consisted of two patients with moderate thrombocytosis who were without thrombotic symptoms and who had normal protein S and protein C and normal fibrinolysis. The second group consisted of two patients with mild to moderate thrombocytosis and thrombosis. Both these latter two patients had abnormalities in protein S. The first patient had only 31% free protein S and 67% total protein S, with normal protein C and normal fibrinolysis. Following treatment, vasoocclusive symptoms resolved and platelet count decreased, but protein S remained low (28% free protein S). The second patient in this group had only 35% total protein S at initial study. Other hemostatic abnormalities were also present. Following treatment, symptoms resolved and protein S returned to normal. Based on this limited series, it appears that, in some patients with ET, thrombotic phenomena may be due to the presence of a second hemostatic abnormality in addition to the high platelet count and abnormal platelet function. This abnormality may be acquired as part of the disease process. Some of these abnormalities may be corrected following treatment.