Project Abstract Millions of US teens remain at risk of developing human papillomavirus (HPV)-related cancers due to inadequate HPV vaccine uptake, despite strong endorsement in clinical guidelines and substantial prior intervention efforts. A 2018 national survey showed that HPV vaccine complete series coverage for teens age 13-15 years was only 50%, far below the 80% target of Healthy People 2020. Prior research has identified strong provider recommendation as the most powerful facilitator of HPV vaccine uptake. Yet, little is known about how to leverage this and other facilitators. Additionally, studies have also revealed multilevel, multifactorial barriers to improving HPV vaccination including negative parental perceptions and limitations of health system support. Furthermore, evidence suggests that HPV vaccine barriers can vary across demographic subgroups, communities and clinics. Despite this knowledge, many prior intervention studies focus on single-level, single component interventions, leaving many barriers unaddressed. Of studies that are multilevel and/or multi-component, interventions are often pre-selected to address “typical” barriers but are not responsive to unique local barriers and local context. To address this critical gap, we propose a 3-arm cluster randomized controlled trial (RCT) to compare implementation strategies that are multilevel and multicomponent and guided by in-depth understanding of how multilevel factors in the practice settings modify the impact of key facilitators such as provider recommendation. We will use mixed methods (surveys, interviews, electronic health records) throughout; initially we will evaluate baseline associations between patient-, provider-, and clinic-level factors and variations in HPV vaccination rates and the quality of the provider recommendation (Aim 1). In Aim 2, we will compare the effectiveness of: 1) A novel “local-tailored” implementation strategy, co- designed with local care teams to address local barriers and contexts; versus 2) A “prescribed” strategy, typical of most health systems, that involves pre-specified interventions addressing pre-selected vaccination barriers; versus 3) Usual care. We will evaluate the effectiveness of these strategies on improving HPV vaccination (primary outcome) and strengthening provider recommendation (secondary outcome) as well as analyzing cost effectiveness. We will also study mechanisms of effect of the implementation strategies (Aim 3). Although the need of local tailoring seems intuitive, it is unknown if local tailoring will yield superior outcomes that could offset the extra investment required, supporting the need for this RCT. We will conduct the study within Kaiser Permanente Southern California, one of the largest community-based pediatric care organizations in the US. Our study will be guided by the Consolidated Framework for Implementation Research and the Multilevel Factors Across the Cancer Care Continuum framework. Completion o...