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The presence of free severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) nucleocapsid‐antigen in sera (N‐antigenemia) has been shown in COVID‐19 patients. However, the link between the quantitative levels of N‐antigenemia and COVID‐19 disease severity is not entirely understood. To assess the dynamics and clinical association of N‐antigen sera levels with disease severity in COVID‐19 patients, we analyzed data from patients included in the French COVID cohort, with at least one sera sample between January and September 2020. We assessed N‐antigenemia levels and anti‐N IgG titers, and patient outcomes was classified in two groups, survival or death. In samples collected within 8 days since symptom onset, we observed that deceased patients had a higher positivity rate (93% vs. 81%; p < 0.001) and higher median levels of predicted N‐antigenemia (2500 vs. 1200 pg/mL; p < 0.001) than surviving patients. Predicted time to N‐antigen clearance in sera was prolonged in deceased patients compared to survivors (23.3 vs 19.3 days; p < 0.0001). In a subset of patients with both sera and nasopharyngeal (NP) swabs, predicted time to N‐antigen clearance in sera was prolonged in deceased patients (p < 0.001), whereas NP viral load clearance did not differ between the groups (p = 0.07). Our results demonstrate a strong relationship between N‐antigenemia levels and COVID‐19 severity on a prospective cohort. [ABSTRACT FROM AUTHOR]