© Meharry Medical College. Objective. To describe the epidemiology of neonatal abstinence syndrome (NAS) in a 16-county Appalachian area of eastern Tennessee. Methods. The Tennessee Surveillance System for NAS provided data on maternal sources of opioids. Data linking hospital discharge diagnosis for NAS to birth certificate data allowed us to compare maternal, delivery, and infant characteristics for NAS births with those for non-NAS births. Results. There were 339 cases of NAS in 2013 and 367 in 2014, for NAS rates of 25.5 and 28.5 per 1,000 live births, respectively. When compared with the state overall, mothers of NAS infants in eastern Tennessee were more likely to use opioids that had been prescribed to another person. There were numerous maternal, infant, and delivery characteristics that were significantly different for NAS births compared with non-NAS births. Conclusion. Neonatal abstinence syndrome is epidemic in the eastern Tennessee area of Appalachia, with unique maternal and infant characteristics that have important implications for primary, secondary, and tertiary prevention.