Our in-depth examination of p63 in the broader transcriptomic and genomic context revealed that p63 regulates critical sets of genes and pathways in the HPV infection pathway and HPV-associated malignancy, including PI3K signaling, WNT signaling, and cell cycle control which may inform the clinical differences between the HPV+ HNSCC subtypes. This evidence concerns the gene TP63 and head and neck squamous cell carcinoma.