Colorectal cancer (CRC) screening and appropriate follow-up can reduce incidence and mortality. The US Preventive Services Task Force (USPSTF) recommends CRC screening through a variety of invasive and non-invasive tests for individuals aged 50 to 75 years. Evidence-based interventions (EBIs) and other strategies exist to promote CRC screening, but adoption and implementation of these are limited, especially in CHCs. Our hypothesis is that a Hub and Spoke multilevel intervention will be superior to usual care. The hub will be Health Quality Partners of Southern California (HQP), a non-profit organization comprised of 16 CHC systems (spokes), serving 135 rural and urban clinic sites. We propose a 2-phase study to pilot and optimize (Phase I) and rigorously test (Phase II) the Hub and Spoke approach and its impact on CRC screening, follow-up, and usual care. UG3 Planning/Exploratory Phase AIM: Pilot test the feasibility, acceptability, and preliminary outcomes of a multilevel intervention for CRC screening, follow-up, and referral-to-care using a mixed methods approach. The intervention includes HQP hub-based delivery of centralized mailed FIT to patients served by individual CHCs-spokes plus complimentary provider and clinic-level interventions at CHCs, and coordination of a standardized navigation strategy delivered by CHCs for abnormal FIT follow-up. UH3 Implementation Phase. We will conduct a 2-arm pragmatic randomized trial to assess impact of a regionally-developed multilevel intervention to increase CRC screening, follow-up, and referral-to-care among CHC patients. The trial will be guided by the Pragmatic, Robust Implementation and Sustainability Model (PRISM), which includes outcomes from the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework and expands them with contextual constructs. Aim 1. Assess effectiveness of the multilevel intervention based on: 1) improvement in proportion up-to-date with screening 3 years post implementation; 2) proportion with abnormal FIT who complete diagnostic colonoscopy within 6 months; and 3) proportion with CRC completing first treatment evaluation. Aim 2. Evaluate the implementation, scalability, and sustainability of a multilevel implementation strategy. Implementation will be evaluated with a mixed methods approach using the RE-AIM outcomes of Reach, Adoption, and Implementation as well as the PRISM constructs of Intervention Characteristics and Recipients from perspective of multiple stakeholders (i.e. patients, front-line staff, and operational leaders). We will also calculate replication costs. Scalability and Sustainability will be evaluated using the RE-AIM outcome of Maintenance and the PRISM constructs of Implementation & Sustainability Infrastructure and External Environment. Our study will help accelerate progress in CRC prevention in underserved populations by identifying multilevel intervention strategies that are scalable to additional...