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BACKGROUND The increased glutamine metabolism is a characteristic feature of cancer cells. The interconversion between glutamine and glutamate is catalyzed by two glutaminase isoforms, GLS1 and GLS2, which appear to have different roles in different types of cancer. We investigated for the first time the protein expression of GLS1 and GLS2, and their correlation with advanced clinicopathological parameters in head and neck cancers. METHOD Consecutive slides from a tissue microarray comprised of 80 samples ranging from normal to metastatic, were stained immunohistochemically for GLS1, GLS2, HIF-1α or CD147. Following analysis by two expert pathologists we carried out statistical analysis of the scores. RESULTS GLS1 and GLS2 are upregulated at protein level in head and neck tumours compared to normal tissues and this increased expression correlated positively (GLS1) and negatively (GLS2) with tumor grade, indicating a shift of expression between GLS enzyme isoforms based on tumor differentiation. Increased expression of GLS1 was associated with high CD147 expression; and elevated GLS2 expression was associated with both high CD147 and high HIF-1α expressions. The correlation of the GLS1 and GLS2 with HIF-1α or CD147 was strongly associated with more advanced clinicopathological parameters. CONCLUSION The increased expression of GLS1 and GLS2 may be explored as a new treatment for head and neck cancers.