21015 Background: We previously showed that free DNA is present in blood of normal subjects and that the plasma DNA level is higher in patients with esophageal cancer compared to normal subjects. These observations suggest that the plasma DNA level may be a useful molecular marker in the diagnosis of esophageal cancer. We hypothesize that lymphatic and hematogenous spread may result in different plasma DNA levels despite both representing advanced disease. Our aim was to measure and compare plasma DNA levels in normal subjects, patients with localized esophageal cancer, patients with lymph node metastases, and patients with hematogenous spread to solid organs (systemic metastases). Methods: Plasma DNA was measured using PCR in 44 normal subjects, 25 patients with localized esophageal cancer (T1–3, N0, M0), 18 patients with lymph node metastases, and 7 patients with systemic metastases. Results: The 95th percentile of plasma DNA level in normal subjects was 19 ng/ml. The median plasma DNA levels were higher in all 3 groups of patients with esophageal cancer compared to control subjects. While there was no difference between the plasma DNA level in patients with localized esophageal cancer and those with lymph node metastases (median of 5 nodes involved, range: 1–31), patients with systemic metastases had a significantly higher level of plasma DNA compared to patients with lymph node metastases and those with localized esophageal cancer. Conclusion: Plasma DNA levels are elevated in patients with esophageal cancer, whether localized or associated with lymph node metastases. In patients with systemic metastases, a significant additional increase in the plasma DNA level occurs. This suggests that measuring the plasma DNA level is a useful molecular diagnostic tool for detection of disseminated esophageal cancer. [Table: see text] No significant financial relationships to disclose.