Abstract Appalachia has a higher burden of cervical cancer than other regions of the United States. Cervical cancer risk factors and causes are largely known, so evidence-based interventions in health systems addressing those factors and causes can improve cervical cancer incidence and mortality rates. Take CARE (Clinical Avenues to Reach Health Equity) is designed to address three factors strongly associated with cervical cancer and is made up of three evidence-based complementary initiatives focused on HPV vaccination, smoking cessation, and cervical cancer screening: I Vaccinate, Break Free, and The HOME Initiative, respectively. The overall goal is to use implementation science designs to provide an integrated approach to reduce cervical cancer risk among patients of 39 health centers from ten participating systems. The project was implemented in two phases: formative and trial. In the formative phase, community profiles were developed to better understand the cancer burden and resources available. Community members and clinic staff were interviewed about barriers to cervical cancer screening and HPV vaccination and norms about screening, vaccination, and tobacco cessation. Findings informed study materials. Clinic champions were identified, and implementation teams were formed to support the champion role. Details were gathered about facility processes, staffing, patient load, and existing cervical cancer-related activities. Waiting room seating, availability of digital displays, number of exam rooms, and locations for promotional materials and staff trainings were documented through environmental scans. The trial phase was introduced as a delayed group implementation design in ten health systems located in Appalachian counties of Kentucky, Ohio, Virginia, and West Virginia from October 2020 to June 2022. Five systems were assigned to an Early Group and five to a Late Group that would receive the intervention 12 months after Early systems. I Vaccinate was first to be implemented, promoting HPV vaccination in 9–45-year-olds. Health systems receive education materials and providers select strategies and set goals to improve vaccination rates. Break Free was introduced six to eight weeks later and identifies eligible smokers who want to quit in the next six months, providing free smoking cessation counseling and medication to patients. Systems received education on the Ask, Advise, Refer model and could select staff to be trained as Tobacco Treatment Specialists. HOME was the final initiative introduced and focuses on improving cervical cancer screening in underscreened female patients via a mail-based HPV self-sampling program. One year after the first initiative launched, health systems were taught to bundle the initiatives as one program, Take CARE. After this, the Early systems entered a sustainability phase for two years. The process will occur similarly for Delayed health systems but with only one year of sustainability. Analyses will focus on changes in HPV vaccination, smoking cessation, and cervical cancer screening over time. Citation Format: Ryan D. Baltic, Roger Anderson, Mark B. Dignan, Amy K. Ferketich, Mira L. Katz, Stephenie Kennedy, Paul L. Reiter, Electra D. Paskett. Take CARE: An implementation science initiative to reduce the cervical cancer burden in Appalachia [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C099.