Background: Coronavirus disease 2019 (COVID-19) has been associated with coagulation disorders, in particular high levels of D-dimers, and increased frequency of venous thromboembolism (VTE). We explore the association between D-dimers at admission and in-hospital mortality in hospitalized COVID-19 patients with or without symptomatic VTE.Methods: From February 26 to April 20, 2020, D-dimer level at admission and outcomes of patients hospitalized for COVID-19 in medical wards (in-hospital mortality or VTE) were retrospectively analyzed in a multicenter study in 24 French hospitals.Results: Among 2878 patients enrolled in the study, 1154 (40.9%) patients had D-dimer measurement at admission. A receiver operating characteristic (ROC) curve analysis identified D-dimer level above 1128 ng/mL as the optimum cutoff value to predict in-hospital mortality (Area Under the Curve of 64.9% (95% CI 0.60–0.69) with a sensitivity of 71.1% (95% CI 0.62–0.78) and a specificity of 55.6% (95% CI 0.52–0.58) that not differ in the subgroup of patients with VTE during hospitalization. Among 609 (52.8%) patients with D-dimers level < 1128 ng/mL at admission, only 35 (5.7%) deaths occurred during hospitalization. After adjustment, in a cox proportional hazard and logistic regression models, D-dimers above 1128 ng/mL at admission were also associated to a worth prognosis with a OR of 3.07 (95% CI 2.05–4.69, p < 0.001) and an unadjusted hazard ratio of 2.11 (95%CI 1.31–3.4, p < 0.01).Conclusions: D-dimer level over 1128 ng/mL is a relevant predictive factor for in-hospital mortality in COVID-19 hospitalized patients in medical ward, regardless the occurrence of VTE during hospitalization.