OBJECTIVE: We aim to compare the diagnostic accuracy of the different methodologies used in the detection of cell-free human papillomavirus (HPV) DNA in HPV-associated head and neck squamous cell carcinoma detection using bivariate analysis methods. DATA SOURCES: Pubmed, Embase, and Scopus were queried using a broad search strategy to search for relevant studies. REVIEW METHODS: Test characteristics were extracted from 33 studies following literature screening, and underwent analyses utilizing a bivariate approach. Summary statistics were identified for each type of methodology, and forest plots and summary receiver operating characteristic curves were constructed. Bias was estimated using Deek's Funnel Plot and the QUADAS-2 tool. RESULTS: In terms of diagnostic accuracy, digital droplet polymerase chain reaction (ddPCR) based testing exhibited the highest diagnostics odds ratio at 138 (59.5, 318), followed closely by next-generation sequencing (NGS) at 120 (39.7, 362), then by polymerase chain reaction (PCR) at 31.4 (14.4, 68.6), and quantitative PCR at 8.74 (4.63, 16.5). CONCLUSION: NGS and ddPCR are comparable in overall diagnostic accuracy, bringing into question their relative roles in diagnosis and screening. Cost-effective ddPCR assays may serve as useful diagnostic and screening tests in the clinic with their low false positive rates and high sensitivity. However, NGS assays also offer high sensitivity and companion metrics, suggesting they may have a more precise role in disease monitoring. Importantly, assay development and benchmarking need further standardization to improve comparison between assays. Finally, saliva-based testing needs to be further investigated using NGS and ddPCR to further understand its limitations in disease detection and monitoring.