Background: Insufficient adherence to guideline recommended cancer screening undermines the effectiveness of current modalities to improve cancer related outcomes, resulting in an unmet clinical need. Implementation of a convenient blood-based cancer screening option, utilizing a test with high sensitivity and specificity, has the potential to address this unmet need. We aim to evaluate the performance of a blood-based multi-cancer screening test in a population of screen eligible individuals across multiple cancer types, encompassing a diverse representation of racial and ethnic groups. Methods: SHIELD (Screening for High Frequency Malignant Disease; NCT#05117840) is a prospective, observational, multi-center basket study in the United States and Europe designed to recruit individuals undergoing screening across multiple cancer types. The study’s primary objective is to evaluate the performance of a blood-based multi-cancer screening test (GuardantLUNAR-2, Guardant Health, US) to detect cancer in screen-relevant individuals compared to the reference standard cancer screening modality. Each study cohort represents a unique cancer type(s). Eligible individuals consent to whole blood collection within 90 days of the standard of care screening for the respective cancer type. Clinical diagnoses, e.g., cancer, are made per standard of care. Primary outcomes: sensitivity, specificity, negative and positive predictive value of the blood-based multi-cancer screening test. Secondary outcomes: number of screen-detected cancers, early and late-stage screen-detected cancers per 1000 screened individuals. One- and two- year clinical outcomes are collected by implementing HIPAA compliant, patient-level linkage of trial data with real-world data sources (Medidata, USA) to which patients consent subsequent to main study consent. Cohort A: Lung cancer screening. Eligibility is aligned with USPSTF screening recommendations; age 50-80 years with > 20 pack-year smoking history who are current smokers or quit within the past 15 years, without any history of cancer or preinvasive lung lesions, and without recent surgery or trauma. This cohort will enroll 9,000 subjects over 24 months at up to 120 global sites. This cohort was initiated in January 2022. As of January 2023, 94 study sites have been activated with 4,977 individuals consented and 4,866 individuals enrolled (defined as study blood sample collected). To date, 4679/4977 (94%) individuals consented to the linkage process. Cohort A is on track to meet enrollment targets by the end of 2023 and on track for final primary outcome data collection by December 2024. Clinical trial information: NCT05117840.