Updated project metadata. Infection by SARS-CoV-2 and subsequent COVID-19 can cause viral sepsis and septic shock. Our past studies demonstrated that dysregulated systemic proteolysis is associated with the pathological mechanism in bacterial septic shock. Thus, here we perform shotgun proteomics and peptidomics analysis by LC-MS/MS to identify and quantify the circulating protein and peptide profile of COVID-19 patient plasma. Plasma samples from four COVID-19 patients were collected at different time points of their ICU stay, including samples from a patient with COVID-19-induced sepsis and bacterial superinfection. By combining mass spectrometry analysis with enzymatic activity assays, our study elucidates the possible pathological involvement of proteolysis in COVID-19-induced sepsis, with particular insight into the dyregulation of protease-mediated systems, such as the coagulation cascade.