Oral squamous cell carcinoma is one of the most common cancers occurring worldwide associated with significant mortality and morbidity. Despite the early prognostic factors which such as histological tumor grading, staging, the extent of the tumor invasion, and involvement of regional lymph nodes, there is a demand for development of molecular markers which will help in unraveling molecular carcinogenesis associated with OSCC. In the current study, we carried out an in-depth proteomic analysis using high-resolution mass spectrometry to identify the differentially expressed proteins among the types of OSCC FFPE tissues. This resulted in the identification of 2,399 non-redundant proteins expressed differentially across histologically-classified well, moderate and poorly differentiated OSCC specimens.