Background: oral cancer has been associated with several risk factor, such as smoking, alcohol, irritants and irradiation. The presence of HPV in oral cancers suggests that HPV may play a similar role in transforming oral epithelia. Objectives: a significant association was appreciated between infection with human papillomavirus (HPV), squamous cell carcinoma and potentially malignant disorders of the oral cavity, such as leukoplakia, erythro-leukoplakia erythroplakia. This review will attempt to focus on relevant characteristics of HPV, analyze its role in oral cancer and discuss some emerging developments. Methods: from the critical analysis of the current literature, many studies evaluating different markers of exposure and viral activity in tumors were collected. Several studies have investigated the prevalence of HPV in these cancers, but the prevalence of HPV detection varies broadly, depending on the population, combination of sub-sites, typology of specimen and method of detection. Results: the majority of HPV-related cancers contain HPV DNA integrated into the host cell genome and express only two viral genes, E6 and E7, both of which encode oncoproteins. Data published in the literature have provided strong evidence that HPVs may be the cause of a defined subset of head and neck cancers and also an indicator of improved survival. Discussion: while the role of HPV infection in the onset of cervix cancer is now well established, there is little information on the prevalence, determinants and natural history of the infection in the oral mucosa, and further studies are needed to clarify the potential role of HPV in the onset of oral cancer.