Background: Midregional pro-atrial natriuretic peptide (MR-proANP) is a newly described stable fragment of the N-terminal part of pro-atrial natriuretic peptide. We tested the hypothesis that in adults with essential hypertension, plasma levels of MR-proANP would be associated with systolic blood pressure (SBP), pulse pressure, and hypertension severity. Methods: Participants included 1,034 African Americans (65 ± 9 years, 72% women) and 880 non-Hispanic whites (61 ± 9 years, 55% women) belonging to sibships ascertained on the basis of hypertension. MR-proANP was measured by an immunoluminometric assay. Hypertension severity was based on number of hypertension medication classes used and multiples of SBP and diastolic blood pressure (DBP) deviations from 120/70 mm Hg. Generalized estimating equations were used to assess whether plasma levels of MR-proANP were associated with SBP, pulse pressure, and hypertension severity independent of potential confounding variables. Results: In African Americans, after adjustment for age, sex, body mass index, estimated glomerular filtration rate (eGFR), smoking history, diabetes, total cholesterol, high-density lipoprotein cholesterol, medication (β-blocker, statin, and aspirin) use, and previous history of myocardial infarction or stroke, higher MR-proANP levels were significantly associated with greater SBP (P < 0.0001), pulse pressure (P < 0.0001), and hypertension severity (P = 0.0013). The associations were replicated in non-Hispanic whites; after adjustment for the above variables, higher MR-proANP levels were significantly associated with greater SBP (P = 0.013), pulse pressure (P = 0.0006), and hypertension severity (P = 0.028). Conclusion: Plasma MR-proANP may be a marker of arterial stiffness and severity of hypertension in adults with hypertension.