As it is known, HNSCC is a heterogeneous disease entity due to HPV infection status, so we suggest that there are differences in oncogenic pathways, probably in addition to E6 and E7 oncoproteins, related to HPV genes associated with various processes that can modulate the expression of a large number of genes and proteins, including KRT6B and KRT6C, which in response can result in increased keratinization. This evidence concerns the gene KRT6B and head and neck squamous cell carcinoma.