Background: Lung cancer survivors are highly enriched for extensive smoking histories and have an increased risk of subsequent primary cancers, including those of the larynx, mouth and throat, esophagus, pancreas, bladder, thyroid, stomach, small intestine, colon, rectum, and kidney. Guideline-concordant surveillance after definitive treatment for lung cancer consists of periodic chest CT scans, which do not visualize the majority of second malignancies that this population ultimately develops. Disadvantaged and minority patients are diagnosed with recurrence and second primary cancers at later stages due to reduced compliance with survivorship surveillance. To address these issues, we propose utilizing multi-cancer early detection (MCED) liquid biopsies. MCED liquid biopsies are part of a rapidly growing field of research that assesses parallel cancer screening for multiple cancer types with point of care blood, urine, or saliva sampling. We selected a methylation-based screening liquid biopsy for multiple reasons: 1) it has the highest PPV and specificity of any test clinically validated in the multi-cancer detection setting thus far, 2) it produces a tissue of origin, allowing for targeted workup of positive findings, and 3) it requires only a single test, which we believe will minimize attrition among vulnerable populations with decreased access to healthcare. We designed a 9,000-patient prospective, multi-institutional randomized clinical trial to assess the efficacy of liquid biopsy in early diagnosis of recurrence and second malignancies in lung cancer survivors. To ensure over 25% of participants are of minority status, we have recruited multiple community hospitals to the study in partnership with Memorial Sloan Kettering Cancer Center. Patients included in this study are survivors of non-metastatic non- small cell lung cancer, status-post definitive treatment (surgery or radiation) with no evidence of disease for at least one year. Participants will be randomized 1:1 to standard surveillance or standard surveillance plus six-monthly methylation-based liquid biopsy tests over a two-year study period, and strict guidelines on follow-up of positive liquid biopsy testing will be provided to reduce harms from false positives or over-diagnosis. Methods: The primary endpoint of this study is the incidence of late stage cancer (distant recurrence or new primary cancer of stage III/IV). Secondary endpoints include cancer-specific mortality, eligibility for definitive interventions once cancer is diagnosed, and utilization of liquid biopsy versus standard of care scans. This is the first randomized controlled trial of screening liquid biopsy in a survivorship population and the first trial utilizing liquid biopsy in a large minority population.