Objectives We evaluated whether differences in cardiovascular risk factors, as assessed by the Framingham risk scores for stroke and cardiovascular disease (FSRS and FCRS), contributed to disparities in all-cause mortality across race and regional strata of USA. Design Race-region-specific FSRS and FCRS scores were computed for 30,086 REGARDS participants who were recruited between January 2003 and October 2007. They were divided across six regions of the “Eight Americas” and then compared after adjusting for race and sex. Kaplan-Meier curves and hazard ratios for all-cause mortality were estimated between regions, first adjusted for age and sex, and then for the risk scores. Results After adjustment for age, sex, FCRS, and FSRS, there was no difference in mortality among Middle-America Whites versus Low-Income White. However, mortality was lower among Middle-America Blacks (-23%; p = 0.06) and High- Risk Urban Blacks (-24%; p = 0.01) compared to Southern Low-Income Rural Blacks. Compared to Middle-American Whites, mortality was higher among Middle-America Blacks (+39%; p < 0.001), High-Risk Urban Blacks (+35%; p < 0.001) and Southern Low-Income Rural Blacks (+85%; p < 0.001). Conclusion Accounting for cardiovascular risk unmasked a greater disparity in mortality between Blacks and Whites and among Southern Rural Blacks compared to Middle- America Blacks and High-Risk Urban Blacks.