A child with chronic relapsing thrombotic thrombocytopenic purpura (TTP/HUS) had recurrent thrombocytopenia, microangiopathic hemolytic anemia with fragmented erythrocytes, microthrombi in the lung vessels, and renal dysfunction. Assay of von Willebrand factor (vWF)-cleaving protease showed a complete protease deficiency in the patient and subnormal activities in the mother and in two asymptomatic siblings. No inhibitor of vWF-cleaving protease was detected in the patient's plasma. Periodic transfusions of fresh-frozen plasma prevented further acute episodes of TTP/HUS. Specific diagnosis of the constitutional deficiency of vWF-cleaving protease helps to provide successful prophylactic therapy.