Background: The Covid-19 pandemic has caused a significant disruption in healthcare utilization. The halt and delay of CRC screening have led to a substantial decline in CRC screening rates. The backlog and the slow resuming of CRC screening will have significant consequences. Although COVID-19 created challenges in CRC screening, it also presents an opportunity for potential innovative approaches that may improve patient compliance and screening rates, such as a blood-based CRC screening test which can be done at the point of care without preparation. Adherence to CRC screening is poor among vulnerable populations even before COVID-19, and these populations disproportionately receive health care in safety-net settings, such as federally qualified health centers (FQHCs). Thus, FQHCs play a significant role in improving CRC-related outcomes and ensuring health equity. This study will examine patient compliance with CRC screening by offering another option, a blood-based screening test, after failing to complete a stool-based screening test or colonoscopy in six months at three FQHCs. Methods: The study will use a stepped wedge cluster trial design and include an initial period of no exposure. Each FQHC will have a cluster of 10 to 17 primary care clinics. After the initial no-exposure period, two FQHCs will implement a blood-based CRC screening test at their primary care clinics. Another FQHC will follow nine months later. Each FQHC will contribute to exposed and unexposed observations and function as its own control. This study will collect quarterly data to capture the impact, feasibility, and acceptability over time. The primary endpoint will be assessed by calculating the number of participants who, otherwise, will not have participated in the CRC screening. In addition, the effectiveness of the implementation strategies will be assessed since transferring innovations into real-world settings is complex, and practical strategies are critical to accelerating future implementation and assisting decision-making. The study will recruit patients who fail to complete a CRC screening after six months and meet the inclusion criteria: between 45-75 years of age, average risk for CRC, capable of and willing to give informed consent, and willing to provide a blood sample. For eligible patients, a blood-based CRC screening test developed by a CLIA-certified laboratory and made commercially available (Guardant Health, CA) will be offered at no cost. An order will be obtained from the participant’s primary care provider before the blood sample is collected. This study plans to enroll up to 2,400 patients over a 3-year period. Patient compliance is a significant barrier to improving CRC screening, and the key to increasing screening participation is patient acceptance of the screening method. A blood-based screening test may offer an alternative for patients who fail to comply with other CRC screening modalities. Clinical trial information: NCT05536713.