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Background: Endothelial dysfunction, coupled with inflammation, induces thrombo-inflammation. In COVID-19, this process is believed to be associated with clinical severity. Von Willebrand factor (VWF), and a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS-13), are strong markers of endothelial dysfunction. We evaluated the impact of the VWF/ADAMTS-13 fraction on COVID-19 severity and prognosis. Materials and methods: A cohort study including 74 COVID-19 patients, with 22 admitted to the intensive care unit (ICU) and 52 to the medical ward (MW), was carried out. We also evaluated, in a group of 54 patients who were prospectively observed, whether variations in VWF/ADAMTS-13 correlated with the degree of severity and routine blood parameters. Results: A VWF:RCo/ADAMTS-13 fraction above 6.5 predicted in-hospital mortality in the entire cohort. At admission, a VWF:RCo/ADAMTS-13 fraction above 5.7 predicted admission to the ICU. Furthermore, the VWF:RCo/ADAMTS-13 fraction directly correlated with C-reactive protein (CRP) (Spearman r: 0.51, p &lt, 0.0001) and D-dimer (Spearman r: 0.26, p = 0.03). In the prospective cohort, dynamic changes in VWF:RCo/ADAMTS-13 and the CRP concentration were directly correlated (Spearman r, p = 0.0014). This relationship was significant in both groups (ICU: p = 0.006, MW: p = 0.02).Conclusions: The present findings show that in COVID-19, the VWF/ADAMTS-13 fraction predicts in-hospital mortality. The VWF/ADAMTS-13 fraction may be a helpful tool to monitor COVID-19 patients throughout hospitalization.