Human papilloma virus (HPV)-associated head and neck carcinoma is quite heterogeneous and most of the tumors arise in the oral cavity, oropharynx, hypopharynx and larynx. HPV was just recently recognized as an emerging risk factor for oropharyngeal squamous cell carcinoma (OSCC). HPV(+) tumors represent 5-20% of all head and neck squamous-cell carcinomas (HNSCCs) and 40-90% of those arising from the oropharynx, with widely variable rates depending on the geographic area, population, relative prevalence of environment-related SCC and detection assay. Different carcinogenic mechanisms are most likely implicated in cervical and oropharyngeal carcinogenesis. The most certain carcinogenic genotype for the head and neck region and the most common high-risk HPV genotype, HPV-16, is frequently detected in OSCC. A combination of p16INK4A expression and molecular detection of HPV DNA is the gold standard for the viral identification in tissue and exfoliated cell samples. Differences in the biology of HPV(+) and HPV(-) OSCC may have implications for the management of patients. New immunotherapy drugs based on the release of the co-inhibitory receptors, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed-death 1 (PD-1) have currently emerged. The goal of therapeutic cancer vaccination is inculcation of a persistent, tumor antigen-specific T cell response which kills tumor cells. The efficacy of the current HPV vaccines, Cervarix and Gardasil, in preventing HPV-related HNSCC is at present unknown. Treatment de-escalation is recommended as the current management of HPV-induced HNSCCs.