Ectopic expression of Sox8 promotes chemoresistance, CSC properties, and EMT features in chemoresistant HNSCC cells. Knockdown of Sox8 inhibited chemoresistance, CSC properties, and EMT features. Post-treatment with cisplatin reduced the tumor volume in xenograft models with Sox8-knockdown cell lines compared to cisplatin alone or untreated controls. Here, SOX8 is linked to head and neck squamous cell carcinoma.