Purpose <p>Oral Submucous Fibrosis (OSMF) is a potentially malignant disorder with a rising rate of mortality. Therefore, we aimed to identify proteins present in OSMF that are unique to it when compared to healthy oral mucosa, which would aid in early diagnosis.</p> Methods <p>Proteins were isolated from both OSMF and control saliva and tissue samples, each had a group of 10 recruited patients. Isolated proteins were subjected to SDS-PAGE analysis followed by trypsin digestion. Proteins presents were identified through LC-MS/MS analysis which were further validated with the MASCOT database.</p> Result <p>Proteins isolated using subtractive proteomics, Cystatin SN and Cystatin S found common in both OSMF saliva and tissue samples and were completely absent in control group samples. Identified proteins play a combined role in inhibiting collagen degradation within the oral mucosa, a causative factor of OSMF.</p> Conclusion <p>The identification of Cystatin SN and Cystatin S was found common and can be considered as a potential diagnostic marker for early diagnosis of OSMF.</p>