Project Summary/Abstract Background: Substance use disorders (SUDs), which can involve illicit drugs, prescription drugs, or alcohol, are common and result in substantial morbidity and mortality. Unhealthy alcohol and substance use are among the leading causes of preventable deaths in the US, are increasing, and are among the top causes of the shortening life expectancy in the US. Screening for unhealthy substance use is recommended by the US Preventive Services Task Force and other national groups because it can lead to improved health outcomes, yet most primary care practices do not have a system to screen for and manage SUDs. Objectives: (1) to determine if practice facilitation (PF) can achieve rapid implementation of patient-centered outcomes research findings to improve screening for and management of SUDs in primary care and (2) to compare whether learning collaboratives (LC), performance incentives (PI), or their combination can significantly improve the implementation of screening for and management of SUDs in primary care compared with PF alone. Methods: The STop UNhealthy Substance Use Now trial (STUN II) is a multisite 2x2 randomized comparative effectiveness trial that will enroll 48 primary care practices. STUN II will evaluate the comparative effectiveness of the following strategies for the implementation of screening and evidence-based interventions for SUDs in primary care: PF, PF plus LC, PF plus PI, and PF+LC+PI. Assessments will be conducted throughout a 12- month intervention period and at a 12-month post-intervention follow up, to assess sustainment. In addition, a mixed methods evaluation will assess the association between implementation effectiveness and putative moderators (e.g., organizational readiness for change) and mediators (e.g., implementation climate). Potential Impact: The study will produce fundamentally important evidence about the comparative effectiveness of PF, PF plus LC, PF plus PI, and PF+LC+PI on uptake of evidence-based screening and interventions for SUD when delivered to primary care practices. It will also generate scientific knowledge about how contextual factors influence the effectiveness of the various approaches in promoting clinical practice and office systems changes in primary care settings. The results will inform health systems, policymakers, and primary care practices about optimal strategies for implementation of screening for and management of SUDs in primary care.