p38α MAPK, a key therapeutic target in HNSCC can be considered as a prognostic marker and is implicated in response to radiation-therapy (RT). We compared the outcome of treatment viz. RT (group-I) and concurrent-RT (combination of RT with chemotherapy or surgery, group-II) with respect to p38α MAPK in HNSCC. The case-controlled study was performed on 143 HNSCC patients. From these p38α estimation was done thrice only for 104 patients (52 each in group-I and II), at pre, during and post-therapy periods using surface Plasmon resonance (SPR) technology, ELISA and western blot analysis. In HNSCC the over-expressed p38α levels declined after treatments in both the groups. The patients receiving only RT had a lower p38α level than those treated with concurrent-RT (p=0.009). Hence, p38α was found to be responsive to RT in HNSCC and it may be useful in predicting the treatment outcome and further improve the prognosis of disease in addition to clinical parameters.