Von Willebrand Disease (VWD) is associated with significant morbidity as a result of excessive mucocutaneous bleeding symptoms. Early diagnosis and treatment is important to prevent and treat these symptoms. We systematically reviewed the accuracy of diagnostic tests using different cut-off values of VWF:Ag and platelet-dependent VWF activity assays in the diagnosis of VWD. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies. We pooled estimates of sensitivity and specificity and reported patient important outcomes when relevant. This review included 21 studies that evaluated VWD diagnosis.. The results showed low certainty in the evidence for a net health benefit from reconsidering the diagnosis of VWD versus removing the disease in patients with VWF levels that have normalized with age. For the diagnosis of Type 1 VWD, in patients with VWF:Ag <0.30 IU/mL, VWFsequence variants were detected in 75-82% of patients, and for VWF:Ag between 0.30-0.50 IU/mL, VWFsequence variants were detected in 44-60% of patients. A sensitivity of 0.90 (95% CI: 0.83 to 0.94), and a specificity of 0.91 (95% CI: 0.76 to 0.97) were observed for a platelet-dependent VWF activity /VWF:Ag ratio of <0.7 in detecting type 2 VWD (moderate certainty in the test accuracy results). VWF antigen and platelet-dependent activity are continuous variables with an increase in bleeding risk with decreasing levels. This systematic review shows that using a VWF activity/VWF:Ag ratio of <0.7 versus lower cutoff levels in patients with an abnormal initial VWD screen is more accurate for the diagnosis of type 2 VWD.