Hypertension is a complex multi-factorial and polygenic disorder. Nevertheless, most studies have focused on single-gene effects. Furthermore, a majority of these studies have been cross-sectional and diagnosed hypertension using conventional blood pressure (BP) measurements, which are known to be subject to biases, including the so-called white-coat effect. Thus, we performed a longitudinal association study to clarify the effects of polymorphism accumulation on the development of hypertension that is defined on the basis of self-measured BP at home (home BP). In 403 Japanese aged 40-79 years with home normotension (home BP <135/85 mm Hg, and not treated with antihypertensive medication at baseline), we examined the associations of 51 single-nucleotide polymorphisms (SNPs) classically nominated or reported to be associated with hypertension in the Japanese Millennium Genome Project for Hypertension with a 12-year risk of progression to home hypertension (home BP >or=135/85 mm Hg, or start of antihypertensive medication). Out of 51 SNPs, four significantly and independently predicted the risk of progression of home hypertension, even after adjustment for possible confounding factors, including baseline home BP value. These were rs3767489 near the regulator of G-protein signaling 2 (RGS2), rs4961 in adducin 1 (ADD1), rs2236957 in the calcium channel, voltage-dependent, alpha-2/delta-subunit 2 (CACNA2D2) and rs769214 in catalase (CAT). Accumulation of these SNPs significantly improved the predictive values for the development of home hypertension. In conclusion, this longitudinal study, which was based on home BP measurement, showed that accumulation of common polymorphisms reliably predicted the risk of future hypertension in the Japanese general population.