--- - |2+ Objective Appalachia—historically a culturally and politically unique region of the United States—has been effectively ignored by contemporary political scientists. Using a unique measure of Appalachian residence, this article analyzes racial attitudes, religion, and Appalachian opposition to the 2008 presidential candidacy of Barack Obama. Methods I use regression analysis to assess the extent to which Appalachian residents differ in their levels of perceived racial favoritism, identification as born‐again Christians, and frequency of church attendance, as well as whether these variables can mediate the seeming regional effect of Appalachia in a standard vote choice model. Results I first demonstrate higher levels of perceived racial favoritism and, especially, higher levels of a particular type of religiosity in the region. I then assess whether these measures can mediate Appalachian distinctiveness in presidential vote choice. When perceived racial favoritism, church attendance, and born‐again Christian status are controlled for in regression models, Appalachian regional opposition to the 2008 Obama candidacy disappears statistically. Conclusion While race and religion both “matter,” I find it is religion that seems to matter more in explaining Appalachian distinctiveness, particularly relative to traditional southern distinctiveness. This provides a new vantage point from which to assess southern politics debates about subregional variation and the relative roles of race and religion, as well as sets the foundation for further analyses of Appalachia and American politics. - 'Social Science Quarterly, EarlyView. '