Background During a pandemic like COVID-19, hospital resources are constrained and accurate severity triage of the patients is required. Objective The objective of this study is to estimate the predictive performances of candidate biomarkers for short-term worsening (STW) of COVID-19. Design Prospective, multicenter (20 hospitals in Paris) cohort study of consecutive COVID-19 patients with systematic biobanking at admission, during the first waves of COVID-19 in France in 2020 (COVIDeF cohort). Setting and participants Consecutive COVID-19 patients were screened for inclusion. They were excluded in presence of severity criteria defined by either an ICU admission, mechanical ventilation (including noninvasive ventilation), acute respiratory distress, or in-hospital death before sampling. Routine blood tests measured during usual care and centralized systematic measurement of creatine kinase, C-reactive protein (CRP), procalcitonin, soluble urokinase plasminogen activator receptor (suPAR), high-sensitive troponin T (TnT-hs), N terminal pro-B natriuretic peptide (NT-proBNP), calprotectin, platelet factor 4, mid-regional pro-adrenomedullin (MR-proADM), and proendothelin were performed. Outcome measures and analyses The primary outcome was STW, defined by a severity criteria within 7 days. A backward stepwise logistic regression model and a ‘best subset’ approach were used to identify independent association, and the area under the receiving operator characteristics (AUROC) was computed. Results Five hundred and eleven patients were analyzed, of whom 60 (11.7%) experienced STW. Median time to occurrence of a severity criteria was 3 days. At admission, lower values of eosinophils, lymphocytes, platelets, alanine aminotransferase, and higher values of neutrophils, creatinine, urea, CRP, TnT-hs, suPAR, NT-proBNP, calprotectin, procalcitonin, MR-proADM, and proendothelin were predictive of worsening. Stepwise logistic regression identified three biomarkers significantly associated with worsening: CRP [adjusted odds ratio (aOR): 1.10, 95% confidence interval (95% CI): 1.06–1.15 for a 10-unit increase, AUROC: 0.73 (0.66–0.79)], procalcitonin [aOR: 0.42, 95% CI: 0.22–0.81, AUROC: 0.69 (0.64–0.88)], and MR-proADM [aOR: 2.85, 95% CI: 1.74–4.69, AUROC: 0.75 (0.69–0.81)]. These biomarkers outperformed clinical variables except diabetes and cancer comorbidities. Conclusion In this multicenter prospective study that assessed a large panel of biomarkers for COVID-19 patients, CRP, procalcitonin, and MR-proADM were independently associated with the risk of STW. Trial registration ClinicalTrials.gov NCT04352348.