Introduction : In intensive care units, COVID-19 viral pneumonia patients (VPP) present symptoms similar to those of other patients with non-viral infection (NV-ICU). To better manage VPP, it is therefore interesting to better understand the molecular pathophysiology of viral pneumonia and to search for biomarkers that may clarify the diagnosis. The secretome being a set of proteins secreted by cells in response to stimuli represents an opportunity to discover new biomarkers. Aims : Identify secretomic signatures of VPP with those NV-ICU. Methods : Plasma samples and clinical data from NV-ICU (n=104), VPP (n=30) or healthy donors (HD, n=20) were collected at Nantes Hospital (France) upon admission. Samples were enriched for the low-abundant proteins and analyzed using non-target mass spectrometry. Specifically deregulated proteins (DEP) in VPP versus NV-ICU were selected. Combinations of 2 to 4 DEPs were established. Results : The differences in secretome profiles of the VPP and NV-ICU groups were highlighted. Forty-one DEPs were specifically identified in VPP compared to NV-ICU. Five combinations of 3 proteins with a receiver operating characteristic curve presenting an area under the curve of 95.0% were identified. Conclusion: This study identifies five combinations of candidate biomarkers in VPP compared to NV-ICU that may help distinguish the underlying causal molecular alterations.