Background: The USPSTF recently recommended colorectal cancer (CRC) screening for adults aged 45 to 49 years in addition to those aged 50 to 75 years. This guideline update, which increases the number of screen-eligible individuals by ̃19 million, is similar to the recommendation in 2018 by the American Cancer Society (ACS) and is based on the modeling studies that reflect rising CRC incidence rates in younger adults. Currently, only 67% of average-risk individuals over the age of 50 years are up-to-date on CRC screening, and adherence to screening is lower in younger individuals (e.g., 50-54 years). Despite the non-invasive nature of existing stool-based CRC tests, barriers remain to adoption, including a dislike for manipulating stool and a requirement for substantial navigational support. Blood tests may overcome these barriers through ease of sample collection and integration into routine blood work. Methods: Here we describe our prospective, multi-center registrational study for validating a blood-based multiomics test for average-risk CRC screening: PREEMPT CRC. Eligible participants include those aged 45-85 with no known history of CRC or colorectal adenomas who are undergoing CRC screening by colonoscopy. The target enrollment is 25,000 participants, and primary outcome measures are sensitivity for CRC and specificity for advanced colorectal neoplasia, which includes CRC and advanced adenomas. Secondary outcome measures include positive predictive value for CRC, negative predictive value for advanced colorectal neoplasia, and sensitivity for advanced adenomas. Novel recruitment methods have been implemented by combining traditional, site-based recruitment and virtual recruitment using an online web portal, coupled with mobile phlebotomy, to make participation broadly accessible, especially during the COVID-19 pandemic. Participants have been enrolled from 40 states as of August 2021, and virtual recruitment has enabled widespread participation, potentially from any zip code in the continental US. To ensure adequate representation of the intended use population, community organizations, federally qualified health centers (FQHCs), and universities have been engaged to reach underserved and minority patient populations. The study was initiated in May 2020 and to our knowledge will be the largest prospective, multi-center registrational validation study of an average-risk CRC screening test to date. Clinical trial information: NCT04369053.