This article examines the independent and interactive effects of rural status and region of residence on health. Individual level factors related to poverty are also tested, in conjunction with rural and regional residence. Negative health effects of rurality were found only in the South, while positive health effects of rurality were found, but only in the Midwest. The results indicate a cumulative risk of rural and Southern residence for older men and women. Living in a rural place in the Midwestern United States may provide unique sources of health benefit as individuals age, which buffer previously observed rural risks to health overall. The findings are discussed in terms of health policy and interventions.