Oral verrucous carcinoma (OVC) is categorised as a low-grade variant of oral squamous cell carcinoma (OSCC). The aetiology of OVC is unknown, and the suggested role of human papillomavirus (HPV) as a causative factor remains contentious. Distinguishing OVC from OSCC is problematic. The rarity of these lesions also makes them difficult to investigate, so most previous studies have been made on small numbers of cases. The aim of this study is to use next generation (NG) copy number (CN) sequencing to identify OVC and oral verrucous hyperplasia (OVH) genomic features and determine if CN analysis could distinguish between the genomic damage pattern in OVH, OVC, and OSCC lesions. Additionally, this project aims to investigate the transcriptional and genomic changes that occur in OVC and compare them with the alterations that occur in OSCC using NG RNA-seq and whole-exome sequencing. Also, and since a verrucous appearance is suggestive of viral aetiology, this study aims to analyse OVC and OVH lesions for the presence of HPV. A total of 57 OVC and 16 OVH FFPE cases were identified for CN analysis and were analysed for the presence of HPV subtypes and for all known human viruses. The CN karyograms of those cases were compared with 45 OSCC karyograms. Transcriptome and exome sequencing were performed on a subset of OVC cases and the results were compared with OSCC sequencing data (all OSCC data belongs to Pre-cancer Genomic Group). CN results showed that the OVC lacked any of the classical OSCC genomic abnormalities such as gain of 3q and loss of 3p and demonstrated considerably less genomic instability than the OSCC cohort. OVC and OSCC profiles could be clearly distinguished. An HPV-16 sequence was identified in one OVC and one OVH, and an HPV-2 sequence was identified in one OVC out of the 73 cases but with low viral loads. Transcriptome sequencing also identified genes that are differentially expressed between the groups. Exome sequencing showed that OVC patients lacked mutations in any of the genes commonly associated with OSCC (TP53, CDKN2A, NOTCH2 etc.). Taken together, these results lead to the conclusion that no association between HPV infections and oral verrucous lesions. OVC is not a subtype of OSCC, but should be classified as distinct entity. The distinguishing features presented in this project should be of value in diagnosis.