Oral cancer is the sixth leading cause of the cancer-related mortality in Taiwan. More than 90% of oral cancers are oral cavity squamous cell carcinomas (OSCCs). The high mortality rate of OSCC is ascribed to metastasis and local regional relapse of cancer cells, suggesting that identification of proteins involved in migration and chemoresistance of OSCC cells can facilitate development of useful treatment approaches for OSCC. To identify novel targets for improvement of OSCC therapy, we have comparatively profiled the proteomes of primary and relapsed OSCC tissues with iTRAQ-based mass spectrometry. Gene expression of proteins dysregulated in OSCC tissues was further surveyed with the cancer genome atlas (TCGA) database. With the analysis, we have identified proteins differentially expressed in the primary and/or relapsed OSCC tissues. Proteins up-regulated in recurrent OSCC and associated with OSCC survival have been selected for evaluation as potential therapeutic targets of relapsed OSCC.