Von Willebrand disease (vWD) is a common bleeding disorder. Diagnosis requires the demonstration of both clinical and laboratory features consistent with this disorder. Laboratory evaluation is complex, due in part to the variety of assays available and differing opinions regarding the optimum testing methodologies and algorithms required. This study represents a retrospective analysis of cases (n = 497) evaluated in our laboratory in which results for von Willebrand factor (vWF) multimeric analysis, vWF antigen, ristocetin cofactor activity, and collagen-binding activity were available. Results were compared to determine which assay parameters best correlate with one another, alone or in combination, and best correlate with the pattern and distribution of multimers. We demonstrate that performance of vWF activity or antigen assays in isolation can lead to both the overdiagnosis and underdiagnosis of vWD. Incorporation of the collagen-binding assay into the diagnostic algorithm leads to a reduced potential for misdiagnosis or misclassification of vWD and can reduce the number of multimeric analyses required dramatically.