Protease activity has been associated with pathological processes that can lead to cancer development and progression. However, understanding the pathological unbalance in proteolysis is challenging since changes can occur simultaneously at protease, their inhibitor and substrate levels. In this work we combined peptidomics, proteomics and peptidase predictions for studying proteolytic events in saliva associated with oral squamous cell carcinoma (OSCC) prognosis. Our results suggest that cleavage products differentially abundant in the saliva of patients with (N+) or without (N0) nodal metastasis exhibit potential of prognostic value in oral cancer and were are able to discriminate N+ and N0 patients whereas reduced protein levels of peptidase inhibitors might disturb the proteolytic balance in saliva of OSCC patients with poor prognosis