One potential mechanism by which diet and lifestyle may affect chronic disease risk and subsequent mortality is through chronic systemic inflammation. In this study, we investigated whether the inflammatory potentials of diet and lifestyle, separately and combined, were associated with all-cause, all-cardiovascular disease (CVD), and all-cancer mortality risk. We analyzed data on 18,484 (of whom 4,103 died during follow-up) Black and White men and women ≥ 45 years old from the prospective REasons for Geographic and Racial Differences in Stroke study. Using baseline (2003-2007) Block 98 food frequency and lifestyle questionnaire data, we constructed the previously validated inflammation biomarker panel-weighted, 19-component dietary inflammation score (DIS) and 4-component lifestyle inflammation score (LIS) to reflect the overall inflammatory potential of diet and lifestyle. From multivariable Cox proportional hazards models, the hazards ratios (HR) and their 95% confidence intervals (CI) for the DIS- and LIS-all-cause mortality risk associations were 1.32 (1.18, 1.47; P trend <0.01) and 1.25 (1.12, 1.38; P trend <0.01), respectively, among those in the highest relative to the lowest quintiles. The findings were similar by sex and race and for all-cancer mortality, but weaker for all-CVD mortality. The joint HR for all-cause mortality among those in the highest relative to the lowest quintiles of both the DIS and LIS was 1.91 (95% CI 1.57, 2.33) (P interaction <0.01). Diet and lifestyle, via their contributions to systemic inflammation, separately, but perhaps especially jointly, may be associated with higher mortality risk among men and women.