Context: The 420 county Appalachia region has larger numbers of vulnerable populations, higher rates of diabetes and cardiovascular disease, and worse health outcomes than non-Appalachia US. Federally-funded health centers play an important role in serving vulnerable populations and are a major health care provider in the Appalachia region. Objective: To explore differences in quality measures between health centers located in Appalachia and Non-Appalachia health centers. Differences are also explored within the Appalachia region. Study Design: Using 2018 Uniform Data System (UDS) data for Health Center Program Awardees, we explored adjusted and unadjusted quality measures including adult weight screening, diabetes control, tobacco screening, appropriate asthma medications, lipid therapy, use of aspirin, and blood pressure control. Quality measures were adjusted based on health center, patient, and service area characteristics, and t-tests were run to compare differences between Appalachia and non-Appalachia health centers. Setting/Dataset: More than 22.1 million patients served by over 900 Health Center Program Awardees. Outcome Measures: Adult weight screening, diabetes control, tobacco screening, appropriate asthma medications, lipid therapy, use of aspirin, and blood pressure control. Results: Non-Appalachia health centers serve higher percentages of patients who are below 100% poverty, nonwhite, and on Medicaid. Appalachia health centers serve higher percentages of older patients and those on Medicare, and patients have higher rates of diabetes and hypertension compared to non-Appalachia health centers. Appalachia health centers perform better than non-Appalachia health centers for most unadjusted and adjusted quality measures, though only poor diabetes control is significant for adjusted measures. Significant differences exist within Appalachia as health centers located in the southern region perform significantly worse for diabetes control and blood pressure control. Conclusions/Impact on Health Centers: Health centers in Appalachia perform better than non-Appalachia health centers for most quality measures, including diabetes control. Given the disparities in health outcomes for Appalachia compared to non-Appalachia, particularly related to diabetes and cardiovascular disease, increasing access to care for health centers could help to improve heath outcomes in the region.