Abstract As outlined in the NIH Strategic Plan for Data Science, recent advances in computing technology have improved the ability to create interoperable and scalable electronic health record (EHR) integrated software using WebServices (e.g., application programming interfaces, APIs) and cloud-based computing architecture. The current leading standard for health care data exchange is Fast Health Interoperability Resources (FHIR), published by the HL7® working group. FHIR is a specification that provides standardized data models and APIs for managing health care data, and represents a simplification and expansion of earlier HL7 standards. The SMART on FHIR standard allows the integration of apps within a clinical workflow, including contextual embedding, authorization, and single sign-on. As technology evolves, EHRs have increasingly adopted more of a platform role, enabling third-party applications to perform limited functions within the system of record. Interoperable standards-based information systems that facilitate the secure but agile exchange of data are critical to contemporary healthcare delivery. Cloud-based services are widely used in the non-healthcare domain. EHR-integrated digital and mobile health applications must include expanded use of the SMART on FHIR standard and cloud base architecture to allow for scalability and ease of installation across healthcare systems and care settings. Our team, which includes board-certified clinical informaticists and Epic-certified programmers, has deep expertise creating multilevel digital health interventions that target the patient, clinician, and healthcare system to increase the uptake of guideline-recommended cancer screening. In a prior multisite randomized controlled trial, our highly successful mPATHTM-CRC (mobile PAtient Technology for Health-Colorectal Cancer) iPad app doubled the proportion of patients who were screened for colorectal cancer. We are currently conducting a hybrid implementation- effectiveness trial of mPATHTM-CRC in 28 community-based clinics (R01CA218416-A1). As part of the parent award, we determined the best way to integrate mPATHTM-CRC in clinical workflow. We then spent 9 months converting mPATHTM- CRC from a stand-alone iPad app to one that is fully-integrated with Wake Forest’s Epic EHR. To date, we have launched the new EHR-integrated mPATHTM program in 6 of our planned 28 clinics. Prior to COVID-19, over 15,000 patients had used mPATHTM, which identified over 1100 patients who were overdue for CRC screening by a mean of 10 years. The specific aims of this supplement are to: (1) Enhance the mPATHTM-CRC application’s interoperability and decrease EHR- vendor specific dependencies by leveraging WebServices and SMART on FHIR; (2) re-engineer mPATHTM-CRC from a containerized, on-premise architecture to a service-agnostic cloud-based architecture; and (3) validate the interoperable (SMART on FHIR leveraging OAUTH2.0) and cloud-based architecture through rigorous t...