Despite the impressive potential of human papillomavirus (HPV) vaccines to prevent cancer, missed clinical opportunities lead to low HPV vaccine coverage rates in the United States. HPV vaccination rates could be improved by systematically incorporating evidence-based strategies to increase vaccination opportunities in clinical care. Our long-term goal is to increase HPV vaccination rates among boys and girls within the diverse settings of real-world primary care in the United States. The objective of this application is to enhance, implement, and evaluate an existing health information technology (HIT) system in delivering evidence-based vaccination improvement strategies across diverse primary care settings. The central hypothesis is that addressing barriers to HIT system use with strategies consistent with Diffusion of Innovation and implementing the HIT system with quality improvement strategies consistent with Social Cognitive Theory will increase the HIT system's Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) resulting in a large public health impact on preventing HPV-related cancers. The specific aims of this proposal are: (1) Enhance integration of a HPV vaccine HIT system within diverse primary care clinics; and (2) Evaluate the RE-AIM components of our enhanced HIT system with a feasibility trial. To maximize the HIT system's appeal to providers and clinics, three improvements will be implemented: (1) complexity of provider involvement will be reduced by improving the HIT system's efficiency; (2) the HIT system's relative advantage will be increased by automatically linking vaccination records across multiple data sources and including tailored parent and provider decision supports; and (3) the HIT's systems' compatibility will be improved by studying and tailoring workflow. A group-randomized trial of six pair-matched clinics assigned to the enhanced HIT system or control (delayed intervention) will evaluate the HIT system. Clinics will be selected from the One Florida Cancer Control Network: a partnership of 22 hospitals, 416 clinic settings and 3,250 physician providers located in all of Florida's 67 counties and encompassing 39% of Florida's patient population. Implementation will be supported by six theory- and evidence- based quality improvement techniques (i.e., practice facilitation, external and internal provider peer opinion leaders, provider audit and feedback with benchmarking, clinic-wide staff involvement, and provider incentives). The approach is innovative because it advances provider reminders by automatically incorporating vaccine data from multiple sources, engages parents by soliciting and addressing their concerns, aide's providers with tailored supports, and is independent from any one electronic health record system. The proposed research is significant because a HIT system incorporating theory- and evidence-based strategies to facilitate provider recommendation in real-time promises to increase HPV vaccination by reducing missed clinical opportunities. Ultimately, such a system has potential to improve other vaccination goals and expand to additional areas of cancer prevention.