Abstract Background People in rural, socioeconomically distressed areas of the world suffer from marked cardiovascular disease (CVD) disparities. Despite the CVD disparities seen in rural, distressed areas, efforts directed toward CVD risk reduction and prevention are limited. We conducted a randomized, controlled trial to determine the effect of an individualized, culturally appropriate, self-care CVD risk reduction intervention (HeartHealth) compared to referral of patients to a primary care provider for usual care on the following CVD risk factors: tobacco use, blood pressure, lipid profile, body mass index, depressive symptoms, and physical activity levels. Methods The study protocol and intervention were developed with a community advisory board of lay community members, business owners, local government officials, church leaders, and healthcare providers. We enrolled 355 individuals living in Appalachia with two or more CVD risk factors. The intervention was delivered in person to groups of 10 or fewer individuals over 12 weeks. In the first session, participants chose their CVD risk reduction goals. HeartHealth was designed to provide participants with self-care skills targeting CVD risk reduction while reducing barriers to risk reduction found in austere rural environments. The targeted CVD risk factors were measured at baseline and 4 and 12 months post-intervention. Repeated measures data were analyzed with mixed models. Results More individuals in the intervention group compared to the control group met their lifestyle change goal (50% vs 16%, p<0.001). The intervention produced a positive impact on systolic blood pressure (p=0.002, time X group effect), diastolic blood pressure (p=0.001, time x group), total cholesterol (p=0.026, time x group), high density lipoprotein (p=0.002, time x group), body mass index (p=0.017, time x group), smoking status (p=0.01), depressive symptoms (p=0.01, time x group), and steps per day (p=0.001, time x group). Compared to the control group, improvement was seen at 4 months in these risk factors and the positive changes were maintained through 12 months. There were no differences seen across time by group in low density lipoprotein or triglyceride levels. Conclusion Interventions like HeartHealth that focus on self-care and that are derived in collaboration with the community of interest are effective in medically underserved, socioeconomically distressed rural areas. Acknowledgement/Funding Patient Centered Outcomes Research Institute