Purpose: Relative to White adults, Black adults have a substantially higher prevalence of hypertension and diabetes, both key risk factors for stroke, cardiovascular disease, cognitive impairment, and dementia. Blood biomarkers have shown promise in identifying contributors to racial disparities in many chronic diseases. Methods: We outline the study design and related statistical considerations for a nested cohort study, the Biomarker Mediators of Racial Disparities in Risk Factors (BioMedioR) study, within the 30,239-person biracial REasons for Geographic And Racial Differences in Stroke (REGARDS) study (2003-present). Selected biomarkers will be assessed for contributions to racial disparities in risk factor development over median 9.4 years of follow-up, with initial focus on hypertension, and diabetes. Here we outline study design decisions and statistical considerations for the sampling of 4,400 BioMedioR participants. Results: The population for biomarker assessment was selected using a random sample study design balanced across race and sex to provide the optimal opportunity to describe association of biomarkers with the development of hypertension and diabetes. Descriptive characteristics of the BioMedioR sample and analytic plans are provided for this nested cohort study. Conclusions: This nested biomarker study will examine pathways with the target to help explain racial differences in hypertension and diabetes incidence.