To test the hypothesis that the serum and glucocorticoid regulated kinase (SGK1) is of relevance to blood pressure in man, we recruited monozygotic (MZ) (126 pairs) and dizygotic (DZ) (70 pairs) normotensive twin subjects and parents of DZ twins. Blood pressure was measured in a controlled fashion recumbent, sitting, and upright. We documented genetic variance on blood pressure in all positions. We then relied on microsatellite markers at the SGK1 gene locus (D6S472, D6S 1038, and D6S270) and two single nucleotide polymorphisms within the SGK1 gene. We found significant linkage of the SGK1 gene locus to diastolic blood pressure (p<0.0002) and suggestive evidence for linkage for systolic blood pressure (p<0.04), documenting the locus as a QTL for blood pressure. We next performed association, using all DZ twins and an MZ member from each pair. We found significant associations between both SNP variants and blood pressure, as well as a significant interaction between the SNPs enhancing the effect. This combined effect of the polymorphisms was confirmed in an independent sample of 260 young normotensive men. These data, coupled with our earlier observations linking the insulin-like growth factor-1 gene locus to blood pressure lead us to conclude that the SGK1 gene is relevant to blood pressure regulation and probably to hypertension in man.