Background SARS-CoV-2 is associated with significant mortality and morbidity in a subgroup of patients who develop cytokine releasing syndrome (CRS) and the related acute respiratory distress syndrome. Precedent evidence suggests that deficiency of the element zinc can be associated with similar complications as well as impaired antiviral response. Herein, beyond determining the zinc status, we explore the association between the plasma zinc concentration, the development of CRS, and the clinical outcomes in hospitalized COVID-19 patients. Methods We conducted a prospective, single-center, observational study in a tertiary university hospital (CUB-Hôpital Erasme, Brussels). Hospitalized adult patients with PCR-confirmed SARS-CoV-2 infection were enrolled within 72 hours of hospital admission. As a surrogate endpoint for CRS, we assessed the presence and severity of COVID-19-associated hyperinflammatory syndrome, using an additive six-point clinical scale (cHIS) that we independently validated in the current study. We defined the clinical outcomes as the length of hospitalization, the incidence of mechanical ventilation, and mortality. We recorded the outcomes with a follow-up of 90 days from hospital admission. Results One hundred and thirty-nine eligible patients were included between May 2020 and November 2020 (median age of 65 years [IQR, 54 to 77]). Our cohort’s mean plasma zinc concentration was 56.2 mcg/dL (standard deviation [SD], 14.8). The absolute majority of patients (96%) were zinc deficient (<80mcg/dL). The mean plasma zinc concentration was lower in patients with CRS (cHIS ≧ 2) compared to those without CRS (−5 mcg/dL; 95% CI, -10.5 to 0.051; p = 0.048). We observed that the plasma zinc concentration is weakly but significantly correlated with the length of hospital stay (rho = -0.19; p = 0.022). However, the plasma zinc concentration was not significantly associated with mortality or morbidity. Conclusions Markedly, an absolute majority of hospitalized COVID-19 patients are zinc deficient. We found no significant association between zinc plasma concentration and cHIS. We find a weak (reverse) correlation between plasma zinc concentration and the length of hospital stay, but not with mortality or morbidity. As such, our findings do not support the role of zinc as a robust prognostic factor among hospitalized COVID-19 patients. We encourage further studies to explore the role of zinc as a biomarker for assessing the risk of developing a tissue-damaging CRS and predicting outcomes in patients diagnosed with COVID-19.