Background Human papillomavirus (HPV)‐mediated oropharyngeal squamous cell carcinoma is a subset of head and neck cancer with a unique mechanism of carcinogenesis. Local disease is treated definitively with a multimodal approach. Navigating recurrences can be challenging, as they are sometimes indiscernible from de novo primary malignancies. Identification of dynamic biomarkers that are specific to HPV‐mediated disease may assist in disease monitoring. We present a 78‐year‐old man who developed a squamous cell carcinoma in the lung 7 years after completing definitive chemoradiation for his p16+ head and neck squamous cell carcinoma. Methods A novel assay for plasma circulating tumor HPV DNA was employed and provided a tool for longitudinal disease monitoring during therapy. Conclusion We bring attention to a novel assay and highlight its potential for use in the treatment paradigm of HPV‐mediated oropharyngeal carcinoma.