The architecture of Human Papillomavirus (HPV) and its interaction with the host genome in Head and Neck Cancer has not been comprehensively described, even though the nature of the viral genome is potentially associated with patient outcome. The limitation is that Next Generation Sequencing (NGS) is inadequate for resolving large structural changes in the genome. Here we integrate optical genomic mapping (OGM) with NGS to characterize the molecular state of HPV in Head and Neck Cancers. We developed a novel DNA isolation technique to obtain high molecular weight DNA (>150,000 base pairs) from two solid HPV positive oropharyngeal tumors. DNA was fluorescently labeled using a site-specific DNA binding protein to create a “molecular barcode” and then imaged and analyzed on the Bionano Saphyr to construct a tumor genome assembly. Parallel samples were processed for NGS. Tumor 1- HPV33 integrated into the human genome on chromosome 15. Following integration, a duplication of the region containing the integrated viral genome occurred, which created a second copy of integrated HPV33. The tumor also exhibited extreme genomic instability with an unusually high number of reciprocal translocations, including one that disrupted pRb. Tumor 2- HPV16 was identified in the tumor sample, with 19 copies of the viral genome per cell. No virus/human chimeric reads were identified, suggesting an episomal viral genome. No structural variations were detected. This study established OGM with NGS can identify the nature of viral association with the cancer genome and determine the structure of potential viral integration sites. We anticipate that the addition of OGM to NGS in the analysis of HPV cancers will allow us to develop tailored treatment de-escalation plans for patients who are at a low risk for cancer recurrence, thereby reducing patient morbidity.