Over the last decade, Scotland has witnessed a rising incidence in squamous cell carcinomas of the head and neck (HNSCC), a phenomenon thought to be linked to infection with high-risk Human Papillomavirus (HPV). HPV-associated HNSCC are a distinct disease presenting unique epidemiological, biological and clinical challenges. However, establishing HPV-related disease is impaired by non-standardised testing protocols and lack of a consensus on the efficacy of existing biomarkers such as p16. This is further complicated by the absence of additional biological markers and a dearth in our understanding of the molecular mechanisms underlying HPV-driven tumourigenesis. While HPV positivity is more commonly detected in the oropharynx, its prevalence and clinical impact in other head and neck subsites remains largely unexplored. The research presented in this thesis was undertaken to determine the prevalence of high-risk HPV in a heterogeneous cohort of 293 HNSCC patients from Tayside and to evaluate the validity of EBP50, a scaffolding protein involved in cell polarity which is targeted by high-risk HPV, as a potential marker for HPV-driven HNSCC. The p16 status of the patients in the cohort was already known and tissue specimens were genotyped for HPV using PCR. HPV infection, defined as p16 positivity and a positive HPV DNA status, was identified in 14% of the cohort. The majority (83%) of the HPV-positive tumours involved the oropharynx while the oral cavity, pharynx and the nasal cavity (17%) were involved to a much smaller extent. High-risk HPV type 16 was the most prevalent HPV type. Patients with HPV-positive tumours had significantly improved overall survival (OS) (2 year OS, 77% vs 57%) and recurrence free survival rates (RFS) (2 year RFS, 92% vs 77%) compared to patients with HPV-negative tumours. A positive tumour HPV status was found to be an independent prognostic indicator (HR 0.216; 95% CI 0.06 – 0.771) and so, given the high morbidity and debilitating physical and psychological problems associated with prevailing aggressive treatment regimens, it is imperative that this knowledge is harnessed to develop and improve treatment strategies. EBP50 expression was evaluated, by immunohistochemical analysis, first in normal oral mucosa and followed up in a smaller subset of 156 HNSCC patients from the main cohort. In the normal tissue EBP50 expression was predominantly membranous. In the tumour samples four distinct EBP50 expression patterns were observed and, of these, weak/ negligible cytoplasmic EBP50 expression showed a strong correlation, only marginally lower than p16 overexpression, with HPV DNA status and was observed largely in patients with tumours of the oropharynx and no history of smoking. Absence of EBP50 expression in the plasma membranes of tumour cells was a recurring pattern in a majority of the tumour samples. The scale of this study, comprising a Tayside cohort of unprecedented size, will undoubtedly contribute to the existing knowledge of HPV incidence in head and neck cancer in Scotland. Furthermore, this study presents compelling preliminary evidence for further researching weak/negligible cytoplasmic EBP50 expression as being a potential indicator of HPV-positivity in HNSCC.