Serine/threonine kinase 39 (STK39) gene has been reported to be a hypertension-susceptibility gene by a recent genome-wide association study in Western populations. To validate this finding in Chinese, we focused on five well-characterized common polymorphisms in STK39 gene to examine their potential association with hypertension in a large northeastern Han population. This is a hospital-based case-control study involving 1009 hypertensive patients and 756 normotensive controls. Data were analyzed by the Haplo. Stats and multifactor dimensionality reduction (MDR) softwares. The genotype and allele distributions of rs6749447, rs3754777 and rs6433027 differed significantly between patients and controls (P < 0.001) even after the Bonferroni correction. The majority of derived haplotypes also showed remarkable differences between the two groups (P <= 0.001). As indicated by MDR analysis, a three-locus model including rs6749447, rs35929607 and rs3754777 was selected as the overall best with a larger testing accuracy of 0.7309 and a maximum cross-validation consistency of 10 (P, 0.001). The utility of this model was reinforced by a Logistic regression analysis. Taken together, our findings suggest the potential interactive role of STK39 gene multiple polymorphisms in the development of hypertension among northeastern Han Chinese.