Circulating cell-free DNA (cfDNA) has been widely used as a prognostic marker for different cancers. : In this study, we used 30 cfDNA samples from oral squamous cell carcinoma (OSCC), 199 public OSCC samples, and 192 normal samples to study various correlation factors that could improve the early-stage diagnostics and/or prognosis of OSCC. : The statistical correlation between healthy and OSCC patients was done and deep sequencing analyses was performed to study various genomic alterations likes copy number variation (CNV), and single nucleotide variants (SNVs), gene fusion and genomic integration of viruses. : We found that the OSCC patient cfDNA concentration can serve as an indicator of tumor stage, malignancy, and survival prognosis. Deep genome sequencing of cfDNA revealed genomic alterations, such as CNVs, fusion genes, and viral integrations. The CNV analysis suggested a correlation with amplification and deletion in chromosomes at loci 1q, 2q, 3p, 3q, and chromosome 8 at loci q22. Moreover, at these loci, amplification of , , and other genes related to keratinization in OSCC patients was observed. In addition, we identified a novel abundant fusion gene, , in seven high-grade tumor samples. The parental genes of this chimera, and , are known to play roles in tRNA modification and DNA repair, respectively. We have identified SNVs in our OSCC cohort. Some of these SNVs, like , , and , have been identified as common cases in different cancer populations. Finally, we detected contigs integrations of human papillomavirus, simian virus, and enterovirus in the OSCC samples, which may point to the potential causes of OSCC. : Our results indicate that the liquid biopsy technique may thus serve as a sensitive tool to study OSCC patient genomic alterations by exploring cfDNA circulating in the plasma, providing an easy-to-use blood test in the future.