Hypercoagulability and endothelial dysfunction are strongly involved in the worsening of the clinical condition in COVID-19 patients. In severe cases, the inflammatory process triggers the release of angiopoietin 2, which could decrease circulating thrombomodulin (TM), a major regulatory mechanism in thrombin generation. Although some studies have described an increased TM resistance, further data are needed to obtain robust results. The objective of our study was to evaluate TM resistance in hospitalized COVID-19 patients using the thrombin generation test and its correlation with development of any severe clinical events (SCE). Forty-seven hospitalized COVID-19 patients were included (median age was 59 years (50-75); 42.6% women). Measurement of endogenous thrombin potential (ETP) revealed that 54.8% of patients had a percentage (%) of ETP inhibition < 40%, suggesting TM resistance. 23% (23%) of patients (n = 11/47) presented at least one SCE. Significant resistance to TM was observed in patients with SCE: percentage (%) of ETP inhibition was 24.3% vs. 47.6% (p = 0.019) in the non-SCE group. Furthermore, lower percentage (%) of ETP inhibition significantly correlated with increased clot stiffness (r= -0.372, p = 0.0167). The percentage (%) of ETP inhibition was a strong predictor of SCE, with an AUC of 0.803 (95%CI: 0.670-0.936). To conclude, thrombin generation can be a powerful tool for risk stratification in hospitalized COVID-19 patients. In addition, increased TM resistance, quantified by a lower percentage (%) of ETP inhibition is strongly associated with the development of SCE and shows promise as a powerful and new independent marker of poor prognosis.