Laboratory tests recommended to screen patients with mucosal bleeding for hemostatic disorders generally include determinations of prothrombin time, partial thromboplastin time, platelet count, and bleeding time. To determine the best tests to identify patients with von Willebrand disease (vWD), we reviewed the laboratory studies of 24 children with vWD and performed receiver operating characteristic analysis on the diagnostic studies. The vWD disease diagnostic tests included determinations of vWF activity (ristocetin cofactor activity), vWF factor antigen, and factor VIII procoagulant (VIII:c). The diagnosis of vWD required the presence of a personal and family history of bleeding symptoms and a documented abnormality of vWF activity or vWF antigen. vWF activity, vWF antigen, factor VIII:c and blood type were determined in 104 symptom-free children. There were no differences between patients and normal subjects for age, gender, or blood type. The bleeding time was abnormal in 43%, the partial thromboplastin time was abnormal in 25%, and either one or both were abnormal in 58% of the patients. The vWF activity, vWF antigen, and factor VIII:c were abnormal in 79%, 58%, and 33%, respectively. Receiver-operated-characteristic analysis showed the vWF activity to be superior to either the vWF antigen or factor VIII:c in establishing the diagnosis of vWD. The combination of the activity, bleeding time, and partial thromboplastin time successfully identified 92% of the patients as abnormal. Determination of vWF activity should be included routinely in the evaluation of hemostasis in children with symptomatic disease.