Background: Cancer is a leading cause of premature death globally. Early detection can reduce cancer mortality by reducing the number of cancers diagnosed at a late stage. A blood-based MCED test (Galleri) was developed that can detect cancer signals and predict cancer origin with a single blood draw. The NHS-Galleri trial is a randomized controlled trial (RCT) assessing the clinical utility of this MCED test in a targeted screening population alongside current screening programs. Screening adherence is lower among certain individuals (eg, those with lower socioeconomic status), despite healthcare being free at the point of access in England. NHS-Galleri utilizes innovative strategies to optimize equity in study recruitment, with the goal of enrolling a representative sample. Methods: This pragmatic, blinded RCT is currently enrolling 140,000 asymptomatic participants by inviting ̃1.3 million residents aged 50-77 in select postcodes of England via the NHS DigiTrials service. Regions were selected to include areas of high cancer mortality, socioeconomic deprivation, and ethnic diversity; eligible participants will be identified from these regions. A variety of methods are employed to enroll a representative study population (defined as including a reasonable number of participants from all socioeconomic statuses and all major ethnic minority groups). These methods include the use of mobile phlebotomy clinics that facilitate access in economically deprived areas, monitoring of participant representativeness by postcode with dynamic adjustment of enrollment, providing interpreters and wheelchair accessibility, and targeted local campaigns. Blood will be collected at 3 annual visits (baseline, year 1, year 2) unless cancer is diagnosed. After baseline blood collection, participants will be randomized 1:1 to the intervention (blood sample analyzed by the MCED test) or control (blood sample stored for potential future MCED testing) arm. Only participants in the intervention arm with “cancer signal detected” will have results returned and be referred for investigations and possible treatment. Participants in the intervention arm without “cancer signal detected” and all in the control arm will remain blinded and return for annual visits. All participants will be reminded to continue guideline-based screening and report unusual/concerning symptoms to a doctor. The primary study objective is a significant reduction in the absolute numbers of stage III & IV cancers diagnosed in the intervention versus control arm 3.5 years after randomization. Cancer-specific mortality will be assessed during trial follow-up. Exploratory endpoints include assessing the primary objective by participant age, gender, socioeconomic status, and ethnicity. Clinical trial information: ISRCTN91431511.