It has long been wondered if viruses cause cancer via a “hit-and-run” mechanism. We examined this in HPV-driven oropharyngeal cancer (OPC) using CRISPR to delete the viral oncogene, E7. Tumours regressed yet regrew over 3 months, despite the lack of E7, and had formed new mutations commonly found in HPV- OPC patient tumours. This is the first biological proof that HPV- OPCs can be formed via a hit-and-run HPV infection.