● SOX2 overexpression is associated with recurrence and contributes significantly to acquiring stem cell traits in HNSCC cell lines● SOX2 expression is high in ALDH1high CD44+cells, and its down-regulation was followed by Oct4 and Nanog down-regulation, decrease in stemness, invasion, EMT, and frequency of CD44+ cells● SOX2 contributes to the resistance of CSCs to cisplatin, and its inhibition decreases CSCs viability, possibly by the inhibition of ABCG2. ● Downregulation of ABCG2 in CSCs overexpressing SOX2 restored drug sensitivity after cisplatin treatment. Here, CD44 is linked to head and neck squamous cell carcinoma.