Background: Population studies have shown that black race is a natriuretic peptide (NP) deficiency state. We sought to assess whether the effects of age, sex, body mass index (BMI) and estimated glomerular filtration rate (eGFR) on N-terminal-pro-B-type NP (NT-proBNP) levels differ in white and black individuals. Methods: The study population consisted of a stratified random cohort from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. The study outcomes were the effects of age, sex, BMI and eGFR on NT-proBNP levels independent of socioeconomic and cardiovascular disease factors. Multivariable regression analyses were used to assess the effects of age, sex, BMI and eGFR on NT-proBNP levels in blacks and whites. Results: Of the 27,679 participants in the weighted sample, 54.7% were females, 40.6% were black, and the median age was 64 years. Every 10-year higher age was associated with 38% [95% confidence interval (CI): 30%–45%] and 34% (95% CI: 22%–43%) higher NT-proBNP levels in whites and blacks, respectively. Female sex was associated with 31% (95% CI: 20%–43%) higher NT-proBNP levels in whites and 28% (95% CI: 15%–45%) higher in blacks. There was a significant linear inverse relationship between BMI and NT-proBNP in whites and a non-linear inverse relationship in blacks. Whites and blacks had a non-linear inverse relationship between eGFR and NT-proBNP. However, the non-linear relationship between NT-proBNP and eGFR differed by race (p = 0.01 for interaction). Conclusions: The association of age and sex with NT-proBNP levels was similar in blacks and whites but the form of the BMI and eGFR relationship differed by race.