Background: We previously reported that a circulating panel of protein biomarkers together with a risk model based on subject characteristics improves lung cancer risk assessment for lung cancer screening compared to current screening eligibility criteria (JCO 2022 PMID 34995129). The goal of this study is to assess cost-effectiveness of a personalized approach to lung cancer screening with LDCT. Methods: We conducted retrospective analyses using data from the US Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial and protein biomarker data measured on prospectively collected pre-clinical sera from the PLCO biorepository. For determination of cost-effectiveness of using the biomarker test for risk based referral for LDCT, we assumed screening of 27.0 million US ever smokers. The reference scenario assumed eligibility using the risk-based smoking approach with no cost. We predicted that the proportion of upcoming lung cancer cases categorized as screening eligible will increase as a result of biomarker-informed eligibility. We used direct NLST costs using 2009 Medicare prices for screening (per person screened), workup (per positive screen), and treatment (per lung cancer case) and evaluated the effectiveness at different biomarker costs. We used life year gained for cases and non-cases, with and without screening. Results: With 80.4% sensitivity at 66.9% specificity; performance of our previously established lung panel, assuming a willingness-to-pay threshold of $70 000 per life-year gained, the biomarker test for referral to screening is cost-effective up to 300$. At a willingness-to-pay threshold of $100,000 per life-year, the biomarker test is cost-effective up to $500. Conclusions: A cost effective blood-based biomarker test has been developed for referral for lung cancer screening with LDCT.