Background: The incidence of human papillomavirus-induced (HPV+) head and neck squamous cell carcinoma (HNSCC), that is, especially oropharyngeal cancers (OPSCC), is increasing, and a significant proportion of patients encounter disease progression. A simple and sensitive test to identify patients with progression is an unmet need. Objective of Review: To systematically review the literature and carry out a meta-analysis of studies, investigating circulating HPV-DNA as a biomarker for disease progression in patients with HNSCC. Type of Review: A systematic review and meta-analysis. Search Strategy: PubMed, EMBASE and the Cochrane Library were systematically searched for articles published in English from January 1980 to November 2017. Search terms used were related to HPV, cancer sites, blood-based biomarkers and terms for specific use settings. Evaluation Method: Articles reviewed and selected by authors and data on study design, demographic variables, location, HPV status, number of pre-treatment blood tests, number of post-treatment blood tests, blood HPV status and number of recurrences and length of follow-up were extracted. A meta-analysis of HPV-DNA as a diagnostic test for recurrence by means of a hierarchical summary receiver operating curve (HSROC) model was performed. Results: We identified 5 studies (n = 600 subjects) examining circulating HPV-DNA in patients with HNSCC. In these 5 studies (n = 411), patients had both pre- and post-treatment blood samples. The pooled sensitivity, in detecting a recurrence, was estimated to be 54% (95% CI: 32%-74%), while the pooled specificity was 98% (95% CI: 93%-99.4%). The pooled false-positive rate is 2% (95% CI: 0.6%-7%). The area under the curve (AUC) of the summary HSROC was 0.93. Positive predictive value was estimated to 93% and the negative predictive value to 94%. Conclusions: Plasma HPV-DNA is a promising tool for surveillance in patients with HPV-related HNSCC, that is, OPSCC, and has a high specificity. By recent technical advances and by increasing follow-up blood samples, the sensitivity could likely be improved.