Background: The Six Building Blocks for improving opioid management (6BBs) is a program for improving the management of patients in primary care practices who are on long-term opioid therapy for chronic pain. The 6BBs include building leadership and consensus; aligning policies, patient agreements, and workflows; tracking and monitoring patient care; conducting planned, patient-centered visits; tailoring care for complex patients; and measuring success. The Agency for Healthcare Research and Quality funded the development of a 6BBs implementation guide: a step-by-step approach for independently implementing the 6BBs in a practice. This mixedmethod study seeks to assess practices' use of the implementation guide to implement the 6BBs and the effectiveness of 6BBs implementation on opioid management processes of care among practices using the implementation guide. Methods: Data collection is guided by the Consolidated Framework for Implementation Research, Proctor's taxonomy of implementation outcomes, and the Centers for Disease Control and Prevention's Guideline for Prescribing Opioids for Chronic Pain. A diverse group of health care organizations with primary care clinics across the USA will participate in the study over 15 months. Qualitative data collection will include semi-structured interviews with stakeholders at each organization at two time points, notes from routine check-in calls, and document review. These data will be used to understand practices' motivation for participation, history with opioid management efforts, barriers and facilitators to implementation, and implementation progress. Quantitative data collection will consist of a provider and staff survey, an implementation milestones assessment, and quarterly opioid prescribing quality measures. These data will supplement our understanding of implementation progress and will allow us to assess changes over time in providers' opioid prescribing practices, prescribing self-efficacy, challenges to providing guideline-driven care, and practices' opioid prescribing quality measures. Qualitative data will be coded and analyzed for emergent themes. Quantitative data will be analyzed using descriptive statistics and clustered multivariate regression. Discussion: This study contributes to the knowledge of the implementation and effectiveness of a team-based approach to opioid management in primary care practices. Information gleaned from this study can be used to inform efforts to curtail opioid prescribing and assist primary care practices considering implementing the 6BBs.