STK39 interacts with OXSR1 and phosphorylates the sodium-chloride co-transporter (SLC12A3), which plays a critical role in regulating the salt/water balance and blood pressure. Here we tested whether STK39, OXSR1, and SLC12A3 genetically contribute to hypertension in the Han Chinese population and how the SNP to SNP or SNP to other risk factors interacts in the pathogenesis of hypertension.Eleven tagging SNPs from STK39, OXSR1, and SLC12A3 were selected and first genotyped in 1210 hypertensive and healthy individuals by sequencing. Two SNPs of STK39, rs6433027 and rs3754777, were found to be associated with hypertension in males (P=0.008-0.024). All other SNPs were not associated with hypertension in either gender. The association of rs6433027 and rs3754777 with male hypertension was validated by genotyping another 4598 hypertensive and healthy individuals. The odds ratios (95% confidence interval, P value) in males were 1.269 (1.13-1.43; P=0.0001) and 1.231 (1.078-1.41; P=0.004) of rs6433027 and rs3754777, respectively. The allele T of rs6433027 presented a strong epistatic effect on the allele A of rs3754777 in hypertensive trait. The minor allele frequencies of two SNPs were not stratified by age, BMI, or diabetes, the three major risk factors for hypertension.Our results suggest that STK39 is an independent risk factor for hypertension in men and that its intragenic SNPs can interact and function in the control of blood pressure.