Liquid biopsy involves testing extracellular DNA (cfDNA – circulating, cell-free DNA) circulating in the blood and deriving from normal or cancer cells. Analysis of a small amount of blood can be a rich source of information about the health status of cancer patient. Liquid biopsy may be an alternative to tumor biopsy, but it presents particular value in cases of inaccessibility of tissue samples and the possibility of repeating it many times. The tumor-derived cfDNA fraction is called circulating tumor DNA (ctDNA) in oncology. An example of ctDNA may be the genome sequences of the Human Papillomavirus (HPV), which is the etiological factor of some head and neck cancers (HNC), in particular of the oropharyngeal cancer (OPC). HPV16 is the most common genotype found in OPC. Noninvasive and frequent determination of HPV16 DNA (ctHPV16) in the blood gives the opportunity to monitor the course of the disease during and after treatment. Very good tools for HPV DNA detection are techniques based on polymerase chain reaction (PCR) like quantitative real-time PCR (qPCR) and digital droplet PCR (ddPCR). The use of these techniques for virus DNA detection in the blood gives high specificity and sensitivity of the analysis. Determination of ctHPV16 after treatment may be helpful in diagnosis of residual disease, which is difficult to assess in radiological imaging. The ctHPV16 biomarker can be successfully used to diagnose the effects of treatment of patients with OPC, which in the future may be helpful in making therapeutic decisions.