Glutathione is a thiol compound that plays an important role in the antioxidant defense system of the celland its deficiency leads to an increased susceptibility to oxidative stress and, thus, progression of many diseasestates including head and neck cancer. In the present study, alterations of glutathione levels were investigatedin study cohort of 500 samples (cohort 1 containing 200 head and neck cancer blood samples along with 200healthy controls and cohort II with 50 head and neck squamous cell carcinoma tissue samples along with 50control tissues) by high performance liquid chromatography. The results indicated that mean blood glutathionelevels were significantly reduced in head and neck cancer patients (p<0.001) compared to respective controls.In contrast, the levels of glutathione total (p<0.05) and glutathione reduced (p<0.05) were significantly elevatedin head and neck squamous cell carcinoma tissues compared to the adjacent cancer-free control tissues. Inaddition to this, pearson correlation performed to correlate different tissue glutathione levels (GSH) with clinical/pathological parameters demonstrated a significant negative correlation between pT-stage and GSH level (r=-0.263**; p<0.01), C-stage and GSH level (r=-0.335**; p<0.01), grade and GSH (r=-0.329**; p<0.01) and gradeversus redox index (r=-0.213**; p<0.01) in HNSCC tissues. Our study suggests that dysregulation of glutathionelevels in head and neck cancer has the potential to predict metastasis, and may serve as a prognostic marker.