In the current study, we report that (1) clinically confirmed HPV-positive head and neck cancers overexpress hBD3, (2) HPV-16 E6 induces hBD3 expression in human oral epithelial cells and oral cancer cell lines when compared to E6 from non-oncogenic HPV types, and (3) this induction appears to be inversely regulated by p53 and induced by ΔNp63α. This evidence concerns the gene TP53 and head and neck cancer.