OBJECTIVE: We evaluated differences in health-related quality of life (HRQoL) for African Americans and Caucasians with self-reported arthritis residing in rural and urban areas of a southern state. METHODS: 1,191 individuals completed a telephone survey, which included the 12-Item Short Form Health Survey (SF-12). Participants were stratified into groups: African American/rural, Caucasian/rural, African American/urban, and Caucasian/urban. We evaluated differences and associations in HRQoL for the four groups. RESULTS: Multivariable linear regression models revealed that being an African American rural resident was associated with worse self-reported mental health on the SF-12 even after adjusting for multiple confounding variables. In contrast, multivariable linear regression models revealed that being a Caucasian rural resident was associated with worse physical health SF-12 scores. CONCLUSIONS: The study revealed differences in HRQoL on the mental and physical health functioning scales of the SF-12 for African American rural and Caucasian rural residents. Researchers assessing HRQoL in arthritis patients should consider using a race/residence product term in their analyses.