Objectives HPV-positive Oropharyngeal squamous cell carcinoma (OPSCC) and Head and neck carcinoma of unknown primary (HNCUP) is increasing. Despite good prognosis, recurrence rates range from 10- to 25%. Surveillance with clinical controls and imaging are not always reliable. Circulating tumour human papillomavirus DNA (ctHPV-DNA) has emerged as a potential biomarker for treatment evaluation and detection of recurrence. We aimed to investigate the correlation between ctHPV-DNA in HPV+ OPSCC/HNCUP and radiologic tumour burden. Additionally, we sought to assess whether ctHPV-DNA could serve as a tool in treatment evaluation. Design A prospective observational cohort study. Setting This multicenter study involved three otolaryngology units located in central Sweden. We utilised HPV genotype-specific assays for droplet digital PCR (ddPCR) to detect ctHPV-DNA in plasma at diagnosis and follow-up. ctHPV-DNA levels were correlated to radiological tumour burden and radiological response using Kendall Rank correlation coefficient and Kruskal Wallis test. Participants Patients with HPV+ OPSCC/HNCUP undergoing definitive (chemo)radiotherapy. Results Out of 54 patients, 51 were eligible for analyses. At baseline, ctHPV-DNA was detectable in 88%. The majority of patients with a favourable radiological evaluation according to RECIST, had a corresponding undetectable ctHPV-DNA at follow-up. The levels of ctHPV-DNA at baseline correlated with Total Tumour Volume and Nodal Volume (r τ = 0.39, p<0.01, respectively r τ =0.26, p<0.01). Conclusion ctHPV-DNA shows correlation with tumour burden. This study strengthens the role of ctHPV-DNA as a promising biomarker for diagnosing and monitoring HPV-related OPC/HNCUP. With further research on serial plasma sampling, ctHPV-DNA could complement radiological treatment evaluation in HPV+ OPSCC/HNCUP.