<p>Cell-free DNA (cfDNA) is emerging as a promising biomarker in liquid biopsy applications for cancer, with growing interest in its potential utility also for the diagnosis, monitoring of treatment response, and detection of relapse in hematologic malignancies. However, the precise origin and clinical relevance of cfDNA in these disorders remain to be fully clarified. In this study, we analyzed plasma samples from 98 patients with hematologic malignancies and 80 healthy donors using quantitative PCR (qPCR) to quantify cfDNA concentrations. We further examined associations between cfDNA levels and clinical parameters, including sex and measurable residual disease (MRD). Our results demonstrated significantly elevated cfDNA levels in patients compared to healthy individuals, with a strong correlation between cfDNA concentration and presence/MRD of the disease. We also identified sex-specific differences in cfDNA levels. Notably, our findings suggest that neutrophils, through the release and degradation of neutrophil extracellular traps (NETs), may constitute a relevant source of circulating cfDNA. In addition, cfDNA concentrations were significantly associated with MRD status, supporting the potential role of cfDNA as a non-invasive biomarker for disease monitoring. Overall, our data highlight the clinical relevance of cfDNA in hematologic malignancies, both as a surrogate for disease burden and as a possible player in disease pathophysiology, thus offering a promising avenue for improved diagnostic and therapeutic strategies.</p>