Context.-Vascular occlusion in sickle cell disease causes increased levels of plasma cell-free DNA as a result of cell death and tissue damage. Objectives.-This study investigates plasma cell-free DNA concentrations in sickle cell disease patients, and aims at exploring the significance of plasma cell-free DNA as a potential biomarker in predicting its complications. Design.-Plasma cell-free DNA levels were measured using real-time quantitative polymerase chain reaction to quantitatively measure b-globin gene in blood samples from 57 sickle cell disease patients with acute vasoocclusive crisis, 42 patients in steady state, 16 individuals with sickle cell trait, and 40 healthy controls. Results.-Plasma cell-free DNA level was significantly elevated in samples from patients with acute vasoocclusive crisis when compared with those in steady state (P<.002), and was significantly higher both in crisis and in steady state when compared with individuals with sickle cell trait and healthy controls (P , .001). There was no difference in cell-free DNA levels between individuals with sickle cell trait and healthy controls. There was no association between plasma cell-free DNA levels and various clinical complications of sickle cell disease and comorbidity. Conclusions.-Plasma cell-free DNA, as quantified by polymerase chain reaction amplification of the b-globin and human telomerase reverse transcriptase genes, is increased in sickle cell disease patients in vasoocclusive crisis and in steady state compared with individuals with sickle cell trait and healthy controls, and may be used as a tool to diagnose and monitor the sickle cell crisis and differentiate post-packed red cell transfusion sickle cell disease patients from individuals with sickle cell trait.