Background: Head and neck squamous cell carcinoma (HNSCC) is a significant global burden. The development of a diagnostic or recurrence monitoring test could evolve from the exploitation of molecular markers such as tumour-specific DNA alterations in plasma. The aim of this study was to report specific genetic alterations of DNA in plasma from HNSCC patients, report the diagnostic accuracy, and discuss potentials for a diagnostic or recurrence monitoring test based on circulating tumour DNA (ctDNA).Methods: A systematic search was performed in PubMed, Embase, and Cochrane Library for articles published in English between 1 January 1980 and 24 October 2018. The search terms used were related to ctDNA methylations and mutations in HNSCC patients.Results: We identified 16 studies from four countries (p = 1156 patients, c = 601 controls) examining ctDNA alterations of HNSCC patients. CtDNA methylations were significantly increased in HNSCC patients compared to controls. Five studies investigated ctDNA mutations in HNSCC. The most frequent examined gene mutation was TP53. Eleven studies investigated ctDNA methylations in HNSCC. Nine studies calculated the diagnostic accuracy of ctDNA methylations in HNSCC compared to controls. The most frequent examined gene methylations were CDKN2A, DAPK1, RASSF1, and P15.Conclusion: We found that increasing the number of ctDNA genetic methylations resulted in an increase in diagnostic sensitivity accuracy. No studies investigating ctDNA mutations included a control group. A combination of multiple human ctDNA gene alterations with viral ctDNA are promising tools for developing a ctDNA biomarker for HNSCC.