Context: Appalachia has been characterized by its poverty, a factor associated with tuberculosis, yet little is known about the disease in this region. Purpose: To determine whether Appalachian tuberculosis risk factors, trends, and rates differ from the rest of the United States. Methods: Analysis of tuberculosis cases reported to the Centers for Disease Control and Prevention's National Tuberculosis Surveillance System (NTSS) within the 50 states and the District of Columbia from 1993 through 2005. Results: The 2005 rate of tuberculosis in rural Appalachia was 2.1/100,000, compared to 2.7/100,000 in urban Appalachia. Urban non-Appalachia had a 2005 tuberculosis rate of 5.4/100,000. Over the 13-year period, tuberculosis rates fell in Appalachia at an annual rate of 7.8%. In one age group (15- to 24-year-olds) the rates increased at an annual rate of 2.8%. Foreign-born Hispanics were the largest racial/ethnic group in this age group. When private providers gave exclusive care for tuberculosis disease, Appalachians were less likely to complete therapy in a timely manner when compared to non-Appalachians (OR 0.6, 95% CI 0.5-0.7). Conclusions: Tuberculosis rates and trends are similar in urban and rural Appalachia. It is crucial for public health officials in Appalachia to address the escalating TB rate among 15- to 24-year-olds by focusing prevention efforts on the growing numbers of foreign-born cases. Due to the increased risk of treatment failure among Appalachians who do not seek care from the health department, public health authorities must ensure completion of treatment for patients who seek private providers.