Objective The abnormal formation and insufficient clearance of neutrophil extracellular traps (NETs) has been reported to be involved in the pathogenesis of lupus nephritis (LN). The abnormal regulation of NETs may contribute to increases in the levels of circulating cell-free DNA (cfDNA). The present study tested the hypothesis that elevated plasma cfDNA levels are related to LN. Methods Fifty-four systemic lupus erythematosus (SLE) patients and 43 control subjects were included in this study. The cfDNA concentrations were measured using the Picogreen Kit, the low-density granulocyte (LDG) percentage in peripheral blood mononuclear cells (PBMCs) was tested using a flow cytometer and the DNase I activity was measured according to the radial enzyme-diffusion method. Results The mean cfDNA concentration in the SLE group was 236.66 +/- 40.09 ng/mL, which was significantly higher than that observed in the healthy control group (187.96 +/- 40.55 ng/mL, p<0.0001). Meanwhile, the mean cfDNA concentration in the patients with LN was significantly higher than that observed in the patients without LN (247.27 +/- 46.79 ng/mL vs. 213.56 +/- 31.34 ng/mL, p= 0.0094), and the mean cfDNA concentration in the patients with active LN was significantly higher than that observed in the patients with inactive LN (254.22 +/- 50.16 ng/mL vs. 215.93 +/- 29.10 ng/mL, p= 0.0349). In the SLE group, the cfDNA concentration was to positively correlate with the quantitative 24-hour urinary protein (r= 0.350, p= 0.013), LDG (r= 0.6361, p= 0.0019) and neutrophil (r=0.5990, p< 0.0001) levels and inversely correlate with the albumin level (r=-0.500, p< 0.0001) and endogenous creatinine clearance rate (r=-0.354, p= 0.044). Compared to that observed in the control group, the SLE group exhibited a significantly increased percentage of LDGs in PBMCs and a significantly decreased DNase I activity. Conclusion Our data indicate that elevated plasma cfDNA concentrations may be associated with active LN and partially attributed to the abnormal regulation of NETs in SLE patients, thus suggesting that NETs constitute an intrinsic link between cfDNA and active LN.