-Abstract Because the early detection of lung cancer by low-dose CT (LDCT) can reduce the mortality, annual LDCT screening is now being reimbursed by Centers for Medicare & Medicaid Services (CMS) for smokers insured through Medicare. However, more than one-quarter of screens discover indeterminate pulmonary nodules (PNs). 4% of PNs are early-stage lung cancers, while the remaining 96% are benign. Therefore, LDCT has over-diagnosis. There is an unmet need for a reflex test for LDCT follow-up to focus care on the 4% smokers need it. The objective of this project is to develop and validate a plasma test for differentiating malignant from benign PNs at baseline LDCT. Future use of this test for discriminating between malignant and benign PNs will complement LDCT for lung cancer detection by reducing the over-diagnosis, and eventually decrease the deaths and cost.