BACKGROUND HER-2/neu is a member of the human epidermal growth factor (HER) family of transmembrane tyrosine kinases, which is significantly associated with the pathogenesis of various cancer types. The aim was to evaluate the expression of HER-2/neu in oral squamous cell carcinoma (OSCC) as a potential biomarker to target antigens for specific immunotherapy in OSCC. METHODS One hundred and forty histologically diagnosed OSCC cases were identified. Four to five-micrometer thick formalin-fixed, paraffin-embedded tumor sections were stained with Haematoxylin and Eosin (H and E). Histological grade was assessed according to WHO/Broders classification, while tumors were staged according to the American Joint Committee on Cancer (AJCC) TNM classification from stage I to IV. Immunohistochemistry was performed by using Rabbit monoclonal antibody against HER-2/neu (EP700Y, cell marquee and diluted 1:50). FISH was performed on positive cases using Vysis PathVysion HER-2 DNA probe (Abbott USA). Probes consist of LSI HER gene spectrum orange and control probe CEP 17 spectrum green. RESULTS In this study, males were mostly effected (64.3%) with buccal mucosa (49%) to be the commonly involved site for OSCC. Majority of cases were moderately differentiated (62.1%) and 50.7% tumors were Stage IV. HER-2/neu was found to be positive (2+) in one case of OSCC, however weak to moderate complete membrane staining was observed in >10% of the tumor cells. One hundred and thirty nine cases were HER-2/neu negative. FISH analysis of HER-2/neu positive cases also showed gene amplification (Her2-neu/ CEp 17 = 225/33 = 7.2). CONCLUSIONS The study showed disparity in the expression of HER-2/neu in OSCC, which is due to multiple reasons. Therefore therapy against HER-2/neu in OSCC is debatable.