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Background: While we strive to live with SARS-CoV-2, defining the immune response that leads to recovery rather than severe disease remains highly important. COVID-19 has been associated with inflammation and a profoundly suppressed immune response., Objective: To study myeloid-derived suppressor cells (MDSCs), which are potent immunosuppressive cells, in SARS-CoV-2 infection., Results: Patients with severe and critical COVID-19 showed higher frequencies of neutrophilic (PMN)-MDSCs than patients with moderate illness and control individuals (P = .005). Severe disease in individuals older and younger than 60 years was associated with distinct PMN-MDSC frequencies, being predominantly higher in patients of 60 years of age and younger (P = .004). However, both age groups showed comparable inflammatory markers. In our analysis for the prediction of poor outcome during hospitalization, MDSCs were not associated with increased risk of death. Still, patients older than 60 years of age (odds ratio [OR] = 5.625; P = .02) with preexisting medical conditions (OR = 2.818; P = .003) showed more severe disease and worse outcome. Among the immunological parameters, increased C-reactive protein (OR = 1.015; P = .04) and lymphopenia (OR = 5.958; P = .04) strongly identified patients with poor prognosis., Conclusion: PMN-MDSCs are associated with disease severity in COVID-19; however, MDSC levels do not predict increased risk of death during hospitalization., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)