Squamous cell carcinoma of the head and neck represent the sixth most common tumor disease. Symptoms usually appears in advanced tumor stages and prohibit an early diagnosis. For decades the incidence and mortality rates stagnate at a stable level. To identify potential biomarker and possible therapeutic approaches tissue samples from tumor patients were compared among themselves and with squamous epithelium samples from non-tumor patients regarding to modified protein expression. By using 2D-DIGE and MALDI-TOF-MS/MS 1874 proteins with repressed or induced expression from 930 protein spots were identified. After deducting the duplicates 591 proteins were kept for the statistical analysis. Some of the biomarker, which were already associated with oropharyngeal cancer, could only be detected indirectly via Ingenuity Pathway Analysis. Besides known tumor markers, like SCCA, CEA and Heat Shock Proteins, as well as established therapeutic approaches, like for example EGFR and PD-1, another potential biomarker were found. These proteins were described partially in context with squamous cell carcinoma of the head and neck region and may be suitable as a diagnostic tool. Annexin A1 acts probably as a tumor suppressor and shows a significant repressed expression in tumor samples compared to healthy squamous epithelium. Against this background Annexin A1 could be possibly used as an early diagnostic marker. Stathmin, a cell cycle regulator, was induced in the comparison between cancer ...