BACKGROUND: Following several waves of the COVID-19 pandemic, we are now facing a lower but persistent rate of SARS-CoV-2 infections, with seasonal resurgences often coinciding with other respiratory tract infections. OBJECTIVE: We aimed to identify early clinico-biological variables predictive of an unfavorable outcome in patients with primary SARS-CoV-2 infection. We also evaluated the role of suPAR, an innovative biomarker, in predicting disease severity. METHODS: We included 255 patients with PCR-confirmed primary SARS-CoV-2 infection and with a 30-day follow-up minimum. Blood samples were collected within the first 24 h of hospitalization to measure suPAR levels. Comprehensive data from medical records were analyzed to assess their predictive value in stratifying patients into seven severity groups, with groups 1 to 3 representing severe COVID-19 (death, intubation, ECMO, or non-invasive ventilation). RESULTS: Early plasma suPAR levels were significantly associated with severe disease progression, as evidenced by ANOVA and logistic regression models, highlighting suPAR as a persistent predictive factor for unfavorable outcomes. CONCLUSION: Our findings suggest that a single suPAR measurement, performed early after a positive PCR test for SARS-CoV-2, holds strong predictive value for patient outcomes. This biomarker, alongside pulse oximetry and CT scan results, could be instrumental in early patient triage during seasonal COVID-19 resurgences.