Importance: Recent studies have suggested that the natriuretic peptide system may be endogenously suppressed in black individuals who are free of prevalent cardiovascular disease. Whether natriuretic peptide levels contribute to racial disparities in clinical outcomes is unknown. Objective: To examine racial differences in N-terminal pro-B-type natriuretic peptide (NTproBNP) levels and their association with all-cause mortality and cause-specific mortality in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Design, Setting, and Participants: Baseline NTproBNP levels were measured in a randomly selected sample of 4415 REGARDS study participants. Those with prevalent cardiovascular disease and renal dysfunction were excluded. From July 1, 2003, to September 12, 2007, among the remaining 1998 individuals, racial differences in NTproBNP levels were estimated, and the percentage difference in NTproBNP levels by race was meta-analyzed and compared with published results on participants free of prevalent cardiovascular disease from the Dallas Heart Study and Atherosclerosis Risk in Communities study, using random effects modeling. The association of NTproBNP levels, race, all-cause mortality, and cause-specific mortality in the REGARDS study was studied using appropriate modeling techniques. Data analysis was conducted from July 1, 2003, to March 31, 2016. Main Outcomes and Measures: Racial differences in NTproBNP levels and association with all-cause mortality and cause-specific mortality. Results: Among the 1998 participants studied (972 women and 1026 men; median age, 63 years [interquartile range, 54-72 years]), median NTproBNP levels in black individuals were significantly lower than those in white individuals (46 pg/mL [interquartile range, 23-91] vs 60 pg/mL [interquartile range, 33-106]; P < .001). With multivariable adjustment, NTproBNP levels were up to 27% lower in black individuals as compared with white individuals (β, -0.32; 95% CI, -0.40 to -0.24; P < .001) in the REGARDS study. In meta-analysis of the 3 cohorts, NTproBNP levels were 35% lower in black individuals than white individuals. Among the REGARDS study participants, for every 1-SD higher log NTproBNP, there was a 31% increased risk of death in the multivariable-adjusted model (hazard ratio, 1.31; 95% CI, 1.11-1.54). This increase was driven primarily by association of NTproBNP with cardiovascular mortality (hazard ratio, 1.69; 95% CI, 1.19-2.41). No interaction between race and NTproBNP levels was observed with all-cause mortality and cause-specific mortality. Conclusions and Relevance: Plasma NTproBNP levels are significantly lower in black individuals as compared with white individuals in the REGARDS study and in pooled results from the REGARDS study, Dallas Heart Study, and Atherosclerosis Risk in Communities study. Higher NTproBNP levels were associated with higher incidence of all-cause mortality and cardiovascular mortality in healthy black and white individuals, and this association did not differ by race.