Clinical expression of COVID-19 infection is widely variable including fatal cases alongside a- or pauci-symptomatic cases with a rapid resolution. We studied saliva from 63 hospitalized COVID patients and from 30 healthy controls by integrating proteomics. peptidomics. and metabolomics to assess the biochemical alterations following the infection and to obtain a set of biomarkers useful for non-invasive diagnosis. We used LC-MS/MS for proteomic and peptidomic analysis and LC-MRM/MS for the analysis of amino acids. The levels of 77 proteins were significantly different in COVID patients. among which 14 proteins were found only in saliva from patients with COVID-19 (7 proteins) or were up-regulated (4 proteins) or down-regulated (3 proteins) at least 5 folds in saliva from COVID patients in comparison to controls. The analysis of proteins revealed a complex balance between pro-inflammatory and anti-inflammatory proteins. and a reduced amount of several proteins with immune activity that possibly favors the spreading of the virus.