© 2017 American Society for Nutrition. Background: Poor diet quality is associated with a higher risk of many chronic diseases that are among the leading causes of death in the United States. It has been hypothesized that evolutionary discordance may account for some of the higher incidence and mortality from these diseases. Objective: We investigated associations of 2 diet pattern scores, the Paleolithic and the Mediterranean, with all-cause and cause-specific mortality in the REGARDS (REasons for Geographic and Racial Differences in Stroke) study, a longitudinal cohort of black and white men and women ≥45 y of age. Methods: Participants completed questionnaires, including a Block food-frequency questionnaire (FFQ), at baseline and were contacted every 6 mo to determine their health status. Of the analytic cohort (n = 21,423), a total of 2513 participants died during a median follow-up of 6.25 y. We created diet scores from FFQ responses and assessed their associations with mortality using multivariable Cox proportional hazards regression models adjusting for major risk factors. Results: For those in the highest relative to the lowest quintiles of the Paleolithic and Mediterranean diet scores, the multivariable adjusted HRs for all-cause mortality were, respectively, 0.77 (95% CI: 0.67, 0.89; P-trend < 0.01) and 0.63 (95% CI: 0.54, 0.73; P-trend < 0.01). The corresponding HRs for all-cancermortality were 0.72 (95% CI: 0.55, 0.95; P-trend = 0.03) and 0.64 (95% CI: 0.48, 0.84; P-trend = 0.01), and for all-cardiovascular disease mortality they were 0.78 (95% CI: 0.61, 1.00; P-trend = 0.06) and HR: 0.68 (95% CI: 0.53, 0.88; P-trend = 0.01). Conclusions: Findings from this biracial prospective study suggest that diets closer to Paleolithic or Mediterranean diet patterns may be inversely associated with all-cause and cause-specific mortality.