Purpose: Previous studies have reported significantly higher concentrations of serum DNA in various types of cancers. Thus the study aims to determine whether circulating free DNA (CFDNA) can aid in the diagnosis and prognosis of oral epithelial dysplasia and oral squamous cell carcinoma (OSCC). Materials and Methods: A nonrandomized case-control study was planned where cases were derived from patients who presented to the KLE Institute of Dental Sciences, Belgaum, India, for evaluation and management of oral lesions between 2007 and 2009. In this study the predictor variable was status of the disease in the patients, and the outcome variable was CFDNA. Demographic variables included age, gender, tobacco consumption, and stage at diagnosis of cancer. Subjects with any known systemic disease, other tumors, or metastatic OSCC were excluded (CFDNA is altered in cases of tissue destruction and inflammatory diseases). The amount of CFDNA was determined through spectrophotometry (Nano-Drop ND-1000 spectrophotometer; Thermo Fisher Scientific, Waltham, MA) in sampled blood and plasma. Mean and range for DNA quantification in plasma and blood were calculated in all groups and compared by use of the analysis of variance test. Results: A total of 390 cases (90 potentially malignant lesions, 150 OSCC cases, and 150 post-treatment OSCC cases) and 150 control subjects were studied. No significant difference was observed in levels of CFDNA in blood between the groups. Similarly, levels of CFDNA in plasma showed no significant difference except between the OSCC and potentially malignant groups, which was probably artifactual. Conclusions: This study shows that disease progression in oral malignancy does not correlate with changes in levels of CFDNA in blood or plasma. (C) 2013 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 71:414-418, 2013