Investigations on some innate immunity proteins can yield misleading information, as investigators often rely on static measurements and assume a direct correlation to function. As protein function is often not directly proportional to protein abundance, and mechanistic pathways are interconnected and under constant feedback regulatory control, functional analysis is required. In this study, we used functional mass spectrometry to measure anti-protease and complement activity in plasma obtained from coronavirus disease 2019 (COVID-19) patients. Our data suggests that within 48 h of hospital admission, COVID-19 patients undergo a protease storm with significantly elevated neutrophil elastase (p <
0.001) and lymphocyte granzyme B (p <
0.01), while, anti-protease activity is significantly increased, including alpha-1 antitrypsin (AAT
p <
0.001) and alpha-1-antichymotrypsin (ACT
p <
0.001). Concurrently, the ratio of C3a to C3beta activity significantly decreased with increasing COVID-19 severity, suggesting more complement activation (Mild COVID-19 p <
0.05
Severe COVID-19 p <
0.001). Activity levels of AAT, ACT and C3a/C3beta remained unchanged over 10 hospital days. Our data suggests that COVID-19 is associated with both a protease storm and complement activation, with the former somewhat balanced with increased anti-protease activity. Evaluation of the AAT/ACT ratio and C3a/C3beta ratio indicated that COVID-19 severity is associated with both neutrophil elastase neutralization and complement activation.