Background: Fire fatality rates have decreased nationally while increasing in Tennessee. Individual characteristics affect the likelihood of fatality. Identification of populations sustaining greater proportions of fire fatality within the State will better inform regional fire prevention activities. Objectives: To compare individual characteristics of fatalities occurring in residential structure fires in Appalachian and Non-Appalachian counties of Tennessee. Methods: Analyses of residential structure fire fatality in Tennessee from 2005 to 2014 were conducted using Tennessee Fire Incident Reporting System data, comparing Appalachian and Non-Appalachian county regions. Analyses were restricted to incidents occurring in noninstitutionalized residential environments. Census data was used to identify county-level demographic characteristics. Direct adjustment for age effects between regions was performed. Results: There was no difference in proportion of fatalities between Appalachian (37.28%) and Non-Appalachian (36.27%) counties. Distribution of gender was similar between regions. A greater proportion of fatalities were aged 65 and older, compared to other age groups. Age- adjusted death rates were higher for Non-Appalachian (13.63/100,000) than Appalachian (11.18/100,000) counties. Age-specific death rates for persons younger than five years was greater in Appalachia (18.06/100,000 vs. 11.94/100,000), while age-specific death rates were greater among Non-Appalachian counties for persons aged 65 and older (37.23/100,000 vs. 19.75/100,000). A greater proportion of fire fatalities occurred in mobile homes in Appalachian counties (18.4%) than Non-Appalachian counties (11.3%). Conclusion: