Introduction: Renalase (RNLS), a novel secreted plasma flavoprotein, has anti-inflammatory effects in a variety of disease processes. Severe COVID-19 disease is associated with disordered inflammatory responses. We hypothesized that reduced plasma RNLS levels could be a marker of COVID-19 disease severity. Methods: Plasma was collected from 51 hospitalized COVID-19 patients and 15 uninfected non-hospitalized controls. Plasma RNLS and cytokine levels were measured and sociodemographic and clinical data were collected from chart review. Data were analyzed using nonparametric analyses and Kaplan Meir curve log rank analysis. Results: Plasma RNLs levels were negatively correlated with inflammatory markers, including IL-1b, IL-6, and TNFa (p = 0.04, p = 0.03, p = 0.01, respectively). Patients with COVID-19 disease had lower levels of RNLS than controls. Lower levels of RNLS were associated with more severe disease among COVID-19 patients. Low RNLS was also associated with worse survival among COVID-19 patients (HR = 4.54; 95% CI: 1.06-19.43; p = 0.005). Conclusion: Low plasma RNLS levels are associated with severe COVID-19 disease and may be a useful additional biomarker when identifying patients with severe COVID-19 disease. Given RNLS anti-inflammatory properties and negative correlation with inflammatory markers, these findings also suggest evidence of a potential pathophysiological mechanism for severe COVID-19 disease.