Head and neck cancer, including oral cancer, is the sixth most common cancer in humans worldwide. Morethan 90% of oral cancers are of squamous cell carcinoma type. Recent studies have shown a strong relationshipbetween human papillomavirus (HPV) infection and head and neck cancer, especially oropharyngeal squamouscell carcinoma (OPSCC) and oral squamous cell carcinoma (OSCC). Moreover, the incidence of HPV-relatedOSCC appears to be on the rise while HPV-unrelated OSCC tends to have stabilized in the past decades. p16, atumor suppressor gene, normally functions as a regulator of the cell cycle. Upon infection with high-risk typesof HPV (HR-HPV), particularly types 16, 18, 31, 33, 34, 35, 39, 51, 52, 56, 58, 59, 66, 68, and 70, the expressionof p16 is aberrantly overexpressed. Therefore, the expression of p16 is widely used as a surrogate marker forHPV infection in head and neck cancer.