The aim of this study is to enhance knowledge regarding the behavior of human papilloma virus (HPV)-associated malignancies between two territories - maxillofacial and otorhinolaryngology. The HPV status and genotype, p16 and p53 expression were performed in 50 patients with malignancies located at the junction between the oropharynx and retromolar trigone alone or oropharynx spread to the junction. These were correlated with the treatment response, prognosis and survival of this kind of tumor located in oral posterior region, marking the transition between two territories (maxillofacial and otorhinolaryngology) of the selected cases. Results showed better treatment outcome and improved prognosis in HPV-positive compared to HPV-negative patients, and a strong link between HPV presence and p16 expression. Multimodal treatment including surgery, radiotherapy and chemotherapy provided the best results, although surgery was only an option in a limited number of cases, due to the advanced stage at presentation and extension in the surrounding tissues, considering the complex anatomy of the area. In the context of the increasing incidence of HPV-positive head and neck cancer, HPV testing together with molecular profiling for p16 and p53 tumor markers could help diagnose malignancies in the initial stages, and also provide important clues towards a targeted, more efficient treatment.