We examined the association of common variants at the NPPA-NPPB locus with circulating concentrations of the natriuretic peptides, which have blood pressure–lowering properties. We genotyped SNPs at the NPPA-NPPB locus in 14,743 individuals of European ancestry, and identified associations of plasma atrial natriuretic peptide with rs5068 (P = 8 × 10⁻⁷⁰), rs198358 (P = 8 × 10⁻³⁰) and rs632793 (P = 2 × 10⁻¹⁰), and of plasma B-type natriuretic peptide with rs5068 (P = 3 × 10⁻¹²), rs198358 (P = 1 × 10⁻²⁵) and rs632793 (P = 2 × 10⁻⁶⁸). In 29,717 individuals, the alleles of rs5068 and rs198358 that showed association with increased circulating natriuretic peptide concentrations were also found to be associated with lower systolic (P = 2 × 10⁻⁶ and 6 × 10⁻⁵, respectively) and diastolic blood pressure (P = 1 × 10⁻⁶ and 5 × 10⁻⁵), as well as reduced odds of hypertension (OR = 0.85, 95% CI = 0.79–0.92, P = 4 × 10⁻⁵; OR = 0.90, 95% CI = 0.85–0.95, P = 2 × 10⁻⁴, respectively). Common genetic variants at the NPPA-NPPB locus found to be associated with circulating natriuretic peptide concentrations contribute to interindividual variation in blood pressure and hypertension.