Background Von Willebrand disease (vWD) is a common bleeding disorder with different subtypes. Laboratory diagnosis is challenging, involving several expensive and complex assays. The von Willebrand factor (vWF) collagen binding assay (VWF:CB) has been described to improve the diagnosis of vWD, but there is a lack of consensus and its implementation into guidelines and diagnostic algorithms is incomplete. Methods A cohort of 88 patients with inherited vWD and 10 patients investigated for vWD due to a bleeding phenotype were recruited and underwent analysis of vWF multimers, vWF antigen (VWF:Ag) and VWF:CB. The total bleeding score (BS) was calculated by using the bleeding assessment tool recommended by the International Society on Thrombosis and Haemostasis. An optimal VWF:CB/VWF:Ag ratio cutoff for differentiating between patients with all multimer sizes and those lacking high molecular weight multimers (HMWM) was established, and the findings were validated in a separate retrospective clinical data cohort. The association between VWF:CB/VWF:Ag ratio and BS was also assessed. Results VWF:CB/VWF:Ag ratio was a very good discriminator of HMWM presence, yielding a sensitivity of 1.0 and a specificity of 0.79 at the optimal cutoff in the validation dataset. VWF:CB/VWF:Ag ratio was a significant predictor of BS (R-2 = 0.39). Conclusion VWF:CB/VWF:Ag ratio is a significant predictor of BS and multimer analysis can be safely omitted in patients with vWD and a VWF:CB/VWF:Ag ratio above 0.6, confirming the VWF:CB assay as an important contributor to vWD diagnosis.