Oral squamous cell carcinoma (OSCC) is one of the most malignant diseases with high prevalence in Taiwan, frequently results in poor prognosis and mortality because of delay diagnosis, tumor recurrence or metastasis. Therefore, early detection and disease monitoring are very important for management in OSCC. Understanding of the systematic fluctuation of salivary proteins caused by tumor lesion formation helps to clarify mechanisms for tumorigenesis and monitor OSCC occurrence. For this propose, patients of OSCC and oral potentially malignant disorders (OPMDs) were recruited to collect their saliva samples in several time points, including within 15 days before treatment, every 3~6 months after treatment, within 15 days before second treatment while OSCC recurrence or malignant transformed, every 3~6 months after second treatment. The quantitative profiling of these longitudinal samples from the same patient were analyzed using TMT protein labelling and 2D-LC-MS/MS. Among 2088 quantified salivary proteins, 54 and 37 were up- and down-regulated between first and second treatments, respectively, and 38 and 8 had trends of up- and down-regulated between before and after treatment consistently. Most of the up-regulated proteins were involved in phosphorylation, acetylation, and cell-cell adhesion; and the down-regulated proteins were involved in exosome and intermediate filament instead. They might be useful as parameters for monitoring malignant levels of oral lesions.