Tumor necrosis factor (TNF) - alpha is multifunctional cytokine that influences the clinical outcome in a number of diseases, including the malignant disease. TNF – alpha is cytotoxic and cytostatic for a variety of tumor cells, including the squamous cell carcinoma of the head and neck. This study was undertaken to evaluate the role of TNF – alpha in the differential diagnosis of malignant and benign tumors, in the follow – up of patients, evaluation of the treatment, and the early detection of recurrence. We also studied the correlation of TNF – alpha levels with the stage and differentiation of the diseases. In this study, the serum levels of TNF – alpha are determined by the immunoenzymometric assay method in fifty patients (group III) with newly diagnosed squamous cell carcinoma of the head and neck regions. In addition, twenty control cases were included, ten cases suffering from benign head and neck diseases (group II), and ten clinically normal subjects of matching age and sex (group I). The serum samples were taken before and after the therapy and the three and six months follow up periods, a fifth sample was collected for the cases showed recurrence after completing the treatment regimen for recurrence. After centrifugation, the sera were stored at –70 degree C until analyzed, and measured by TNF – alpha immunoenzymometric assay, using medgenix (TNF – alpha) EASIA kit. The pretreatment mean value of TNF – alpha in the study group III (818.5 + 331.7 Pg/ml) was almost higher than 100 times the control group I (4.47 + 1.3 Pg/ml), and group II (7.92 + 6.3 Pg/ml). It was also noted that post – treatment mean values were significantly lower than pretreatment mean value in the study group III. Furthermore, a high statistical difference was found between TNF – alpha levels in different degrees of differentiation, tumor size, and stage of the disease. The values were higher in patients with large tumor size, advanced stages, and in poorly differentiated tumors. The cases which had tumor recurrence (14%), showed significant elevation of the serum levels of TNF – alpha after the early post – treatment drop of the serum levels. The serum levels of TNF – alpha could be used to confirm diagnosis of malignancy in conjunction with other clinical and histopathological correlations.Also it could be an indicator for the response to treatment, the follow up, and the early detection of recurrence, especially in cases with post radiotherapy fibrosis, oedema, and infection which may disturb the histopathological pattern of the tissues.