PROJECT SUMMARY Colorectal cancer (CRC) is exerting a significant public health impact in Mexico despite the availability of effective screening strategies. Yet, there are no national CRC screening (CRCS) guidelines or organized CRCS programs in Mexico. We aim to implement a CRCS program in an integrated health system that is context- appropriate, sustainable, scalable, and easily transferable to different health systems in Mexico. We will optimize FIT uptake and CRCS completion by adapting and evaluating evidence-based interventions (EBIs) (patient education, patient reminders, patient navigation); designing implementation strategies (training with technical assistance, practice champions, audit and feedback) to deliver these EBIs; and evaluating the effectiveness, cost-effectiveness, and implementation outcomes using a type 2 hybrid effectiveness implementation study. Our proposed research is potentially groundbreaking and of substantial public health significance in that it will be the first implementation research study in Mexico to address CRCS while applying rigorous implementation science methods. It will advance scientific knowledge on the effectiveness of EBIs that have been developed and tested in other countries and adapted for use in Mexico; it will also study the impact of implementation strategies to deliver them in a real-world setting. Our proposed study will incorporate an economic evaluation of the implementation of the EBIs to provide healthcare institutions with the necessary information to plan for adoption and sustainability in settings with different resources.