Introduction: High-risk Human Papillomaviruses (HPVs) cause a subset of Oropharyngeal cancer (OPCs), with a rising incidence of HPV-OPC in the developed world. This thesis explores the epidemiology and epigenetics of oral HPV infection and OPC. Methods and Results: Systematic Review of 4,365 abstracts and Meta-analysis of 45 studies: Pooled prevalence for any oral HPV infection was 4.9% (95% CI: 3.7%- 6.3%) and high-risk HPV 1.8% (95% CI: 1.2%- 2.6%), with no difference by gender but variability by geography and sample type. Prospective Cohort Study in 1 01 individuals: Oral HPV in oral rinse reduced from 11% before tonsillectomy to 2% afterwards. However, 10% had new infections. Retrospective Review of 28,846 OPC on HES database: Survival is worse with increasing age, poor socio-economic status and multiple co-morbidities (p < 0.05). Genomics and Epigenetics Study on 40 FFPE samples from HPV -OPC: 40% had viral E2 gene disruption detected by PCR, with no differences in methylation at E2-binding sites (E2BS). Conclusions: Oral HPV prevalence is low and tonsillectomy may affect its natural history. 60% HPV-OPC have an intact E2 gene with no differences in E2BS methylation. Survival from OPC depends on age, comorbidities and socio-economic status.