[Abstract] Objective To explore the correlation between plasma cf-DNA in HFRS patients and disease severity as well as plasma HTNV load, analyze sources and characteristics of the cf-DNA, and provide evidences for observing the mechanism of HFRS. Methods The 128 plasma samples from 47 patients in different stages of HFRS and 20 plasma samples from 20 cases of healthy volunteers were collected. We quantitatively detected the total plasma cf-DNA and analyzed the depurated cf-DNA qualitatively. The samples of cf-DNA were detected using high-throughput sequencing and studied by bioinformatics. Results In HFRS patients, the plasma cf-DNA levels peaked at the hypotensive stage, and then decreased gradually. Exclusively in the febrile/hypotensive stage, the plasma cf-DNA levels of severe/critical patients were higher than those of the mild/moderate group. Plasma cf-DNA displayed a low-molecular weight appearance, corresponding to the size of apoptotic DNA. After sequencing, all the cf-DNA reads can mapped onto human genomic DNA. Conclusion The plasma cf-DNA levels were dynamically elevated during HFRS, and correlated with disease stages and severity, which suggests that plasma cf-DNA may be a potential biomarker for the pathogenesis and prognosis of HFRS.