Acute respiratory distress syndrome (ARDS) is the main complication of COVID-19, requiring admission to Intensive Care Unit (ICU). Despite extensive immune profiling of COVID-19 patients, to what extent COVID-19-associated ARDS specifically differs from other causes of ARDS remains unknown. To address this crucial question, we build 3 cohorts of patients categorize in COVID-19negARDSpos, COVID-19posARDSpos, and COVID-19posARDSneg, and compare their immune landscape analyze by high-dimensional mass cytometry on peripheral blood follow by machine-learning based analysis. A cell signature associating S100A9/calprotectin-producing CD169pos monocytes, plasmablasts, and Th1 cells is found in COVID-19posARDSpos, unlike COVID-19negARDSpos patients. Moreover, this signature is essentially share with COVID-19posARDSneg patients, suggesting that severe COVID-19 patients, whatever they experience or not ARDS, display similar immune profiles. We also show an increase in CD14posHLA-DRlow and CD14lowCD16pos monocytes correlate to the occurrence of adverse events during ICU stay. Our study demonstrates that COVID-19-associated ARDS display a specific immune profile, and might benefit from personalize therapy in addition to standard ARDS management. Analyses were performed on a cohort 1 of 63 cryopreserved PBMC samples isolated from 42 patients included in ICU (n = 36) or infectious standard ward (n = 6). All patients but one were classified as severe at admission, requiring oxygen at a flow rate higher than 2 liters/min. ARDS was defined in accordance with international guidelines.34 Patients were classified in 3 groups: COVID-19negARDSpos (n = 12, ARDS stages: 1 mild, 4 moderate, 7 severe), COVID-19posARDSpos (n = 13, ARDS stages: 8 moderate, 5 severe), and COVID-19posARDSneg (n = 17, including 11 from ICU and 6 from infectious standard ward). In the COVID-19posARDSneg, no statistical differences were noticed for immune cell abundance or phenotype between ICU and standard ward patients. Within the COVID-19negARDSpos group, ARDS etiologies were bacterial pneumonia (n = 9), anti-synthetase syndrome (n = 1), and unknown (n = 2). For 21 patients, a second blood sample obtained on day 7 after enrollment was studied (n = 7 for COVID-19negARDSpos, n = 8 for COVID-19posARDSpos, and n = 6 for COVID-19posARDSneg). Additionally, a validation cohort (cohort 2) was set up with 16 patients with demographic data detailed in Table S1 and Table S2. Patients were classified in 3 groups: COVID-19negARDSpos (n = 6), COVID-19posARDSpos (n = 5), and COVID-19posARDSneg (n = 3); additionally, COVID-19negARDSneg (n = 2) samples were included. None of our patients received corticosteroids at the time of the study nor immune-modulators. The presence of SARS-CoV-2 in respiratory specimens (nasal and pharyngeal swabs or sputum) was detected by real-time reverse transcription polymerase chain reaction (RT-PCR) methods. For all files, live single cells were selected by applying a gate on DNA1 versus DNA2 followed by a gate on DNA1 versus Cisplatin, then beads were removed by applying a gate on the beads channel (Ce140Di) versus DNA.1 Normalized, transformed and gated values were exported as FCS files. Included are files from myeloid panel.