In CTN-0076-Ot (Clinical Decision Support for Opioid Use Disorders in Medical Settings: Pilot Usability Testing in an EMR (COMPUTE)), our team iteratively developed and piloted a web-based and electronic health record (EHR)-integrated Opioid Use Disorder (OUD) Clinical Decision Support (CDS) system to offer expert guidance to primary care providers (PCPs) on the diagnosis and management of OUD. The OUD-CDS, referred to as Opioid Wizard, was implemented within the EPIC EHR of one large care system and piloted with 55 providers to ensure content validity and provider satisfaction. Through CTN-0095 (COMPUTE 2.0), our team will now implement Opioid Wizard in a large multi-site clinic-randomized controlled trial to evaluate its impact on practice process measures and patient outcomes. We also aim to prepare for scalability (i.e., integration into usual primary care practice after the study is complete) and dissemination by evaluating facilitators and barriers to implementation, determining the costs of implementation and maintenance, and assessing the short-term cost impacts of Opioid Wizard. The study will include three large diverse care systems and randomize a minimum of 30 clinics to receive Opioid Wizard or usual care (UC). In intervention clinics, Opioid Wizard will identify patients who are at high risk` for OUD or diagnosed with OUD; use data stored in the EHR for each eligible patient to assemble treatment recommendations tailored to each patient’s current needs; display these recommendations to PCPs via the Opioid Wizard user interface; and store analytic data from all targeted visits. In UC clinics, Opioid Wizard will run invisibly in the background to identify high-risk or OUD patients, assemble treatment recommendations tailored to each eligible patient’s needs, and store analytic data from all targeted visits. This study is part of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative bolsters research across NIH to improve treatment for opioid misuse and addiction.