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Simple Summary: Cervix cancer is largely (95%) caused by human papilloma virus (HPV). Curative treatment for locally advanced cervical cancer (progressed beyond the cervix) is chemotherapy and radiotherapy (CRT), followed by internal radiation (brachytherapy). In approximately 30% of patients the cancer will return, usually within 2 years of completing initial treatment. Assessment after CRT is by clinical examination and MRI and PET/CT scans. None of these methods are particularly sensitive for detecting early relapse or discriminating between early relapse and treatment related scarring. Currently, there is no test that can reliably predict early relapse. We have developed a blood test which measures the presence of HPV-DNA fragments in the blood. In this initial feasibility study, we have demonstrated that cHPV-DNA can be accurately detected in the blood before CRT and if present at the end of treatment or detected during follow up, is indicative of tumour relapse. Background: The majority of locally advanced cervical cancers (LaCC) are causally related to HPV. We sought to investigate the utility of an ultra-sensitive HPV-DNA next generation sequencing (NGS) assay—panHPV-detect—in LaCC treated with chemoradiotherapy, as a marker of treatment response and persistent disease. Method: Serial blood samples were collected from 22 patients with LaCC before, during and after chemoradiation. The presence of circulating HPV-DNA was correlated with clinical and radiological outcomes. Results: The panHPV-detect test demonstrated a sensitivity and specificity of 88% (95% CI-70–99%) and 100% (95% CI-30–100%), respectively, and correctly identified the HPV-subtype (16, 18, 45, 58). After a median follow up of 16 months, and three relapses all had detectable cHPV-DNA at 3 months post-CRT despite complete response on imaging. Another four patients with radiological partial or equivocal response and undetectable cHPV-DNA at the 3-month time point did not go on to develop relapse. All patients with radiological CR and undetectable cHPV-DNA at 3-months remained disease free. Conclusions: These results demonstrate that the panHPV-detect test shows high sensitivity and specificity for detecting cHPV-DNA in plasma. The test has potential applications in assessment of the response to CRT and in monitoring for relapse, and these initial findings warrant validation in a larger cohort. [ABSTRACT FROM AUTHOR]