The objective was to evaluate the relationship between two circulating molecular forms of BNP (BNP32 and NT-proBNP), the severity of hypertension (HTN) and cardiac hypertrophy in subjects with mild, moderate and severe HTN. We prospectively studied 78 patients (43 males; mean age 51.4±11 years) with essential HTN and 28 age- and sex-matched controls. BNP32 and NT-proBNP were measured by radioimmunoassay. In grade 1 HTN BNP32 was not elevated and NT-proBNP was reduced (p=0.030) when compared to controls. However, both LogBNP32 and LogNT-proBNP were increased with the severity of HTN from grade 1 to 3 (P for trend 0.0001 and =0.003, respectively). By multivariate analysis, LogBNP32 was independently predicted by age (=0.210, p=0.026) and HTN grade (=0.274 p=0.004), while LogNT-proBNP was independently predicted by sex (=0.235 p=0.012), and HTN grade (=0.218, p=0.0023). Two forms of BNP were measured in normal subjects and patients with essential HTN. In grade 1 HTN, BNP32 was unchanged and NT-proBNP was significantly reduced when compared to controls. As the severity of hypertension increased in humans with grade 1 to 3 HTN, both BNP32 and NT-proBNP levels were increased while not being affected by the presence of LVH. The lack of activation of BNP32 together with the reduction of NT-proBNP in grade 1 HTN may represent an impaired response of the BNP system in the early phase of HTN. The later activation of both forms of BNP may be a late compensatory effect as it correlates to the severity of HTN rather than cardiac hypertrophy/remodeling.