Background: Establishing prognostic factors is very important in treatment of cancer patients. In Head and Neck Cancer-(HNC) patients, diagnosis occurs usually in already advanced disease, therefore, there is a special need to early detect the disease and its recurrence. Aim:We aimed to evaluate the survival (OS, DFS) and its prediction by a panel of serum Tumor Markers: CEA (Carcino Embryonic Antigen), SCC (Squamous Cell Carcinoma Antigen), TPS (Tissue Polypeptide Specific Antigen), CYFRA 21-1 (Cytokeratin 19 Fragment) and sIL-2R (soluble Interleukin 2 Receptor) in HNC patients, for establishing prognosis in those patients. Patients and methods:We evaluated 293 blood samples from 194 HNC patients. Blood Tumor Markers levels were evaluated by conventional ELISA assays, at the first date of diagnosis and during follow-up. Comparison of marker levels between 76 healthy subjects and HNC patients, alive vs dead, response to therapy and survival -were performed.Results: Significantly lower levels of all Tumor Markers were demonstrated in patients alive, as opposed to all those who died. HNC patients who died 0-24 m after entering the study, were found to be the most sensitive time parameter to evaluate, as compared to 0-12 m, 0-36m, 0-48m or 0-60 m. We compared the alive and dead patients according to gender and found more male patients than females. Serum levels of all Tumor Markers of our panel were higher before therapy and decreased significantly thereafter, in patients responding to various therapies. The Tumor Markers sIL-2R and Cyfra 21-1 levels, were best correlated to prediction of patient's survival. Patients having low levels had the best clinical outcome and a longer survival -according to ROC analysis. Conclusion:CEA, SCC, TPS, CYFRA 21-1 and sIL-2R are all useful Tumor Markers in the management of HNC patients. They assessed response to therapy, were prognostic for recurrence earlier than CT and predicted survival. From our panel of Tumor Markers, sIL-2R and Cyfra 21-1, proved to be the most sensitive predictors of advanced disease with poor prognosis vs those with a good and longer survival.