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The purpose of this systematic review is to evaluate IL-6 activity in patients with head and neck squamous cell carcinoma (HNSCC). A systematic review of the association between serum, saliva and tumor IL-6 and HNSCC was developed on PubMed\/Medline in the publication range from January 1995 to January 2019. Our literature analysis demonstrated that overexpression and elevated serum and\/or saliva IL-6 concentrations in patients with HNSCC are related to poor survival and oncological outcomes. Although there is a correlation between IL-6 concentrations and tumorigenicity, it is noteworthy that IL-6 targeted therapies are generally performed in vitro and in experimental studies. 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