Circulating tumor DNA (ctDNA) is a noninvasive, real-time approach that can provide diagnostic and prognostic information for cancer patients before and after treatment. However, only a small fraction of cell-free DNA (cfDNA) fragments originate from tumor cells, while the majority of fragments come from hematopoietic cells. Somatic mutations harbored by hematopoietic cells (clonal hematopoiesis, CH) can be a major source of false positive mutations identified in cfDNA affecting clinical decisions. Therefore, it is critical to characterize and identify somatic mutations by clonal hematopoiesis. Here, we use a cfDNA TruSight Oncology (TSO) assay targeting 500+ genes to show that fragment size distribution of cfDNA released by malignant or healthy hematopoietic cells is different from that of cfDNA released by solid tumors, and develop a method leveraging fragment size distribution to differentiate somatic mutations from different cell origins.