Non-synonymous GRK4 variants, R65L, A142V and A486V, are associated with essential hypertension in diverse populations. This study replicated the association of GRK4 variants, including GRK4142V, with human essential hypertension in a Japanese population (n = 588; hypertensive, n = 486 normotensive controls) and determined whether the presence of GRK4 variants predicted the blood pressure (BP) response to angiotensin receptor blockers (ARBs) in patients with essential hypertension. We analyzed 829 patients and compared the response to ARBs between individuals with no GRK4 variants (n = 136) and those with variants at one or any of the three loci (n = 693). Carriers of hGRK4142V had a greater decrease in systolic BP in response to ARBs than non-carrier hypertensive patients. By contrast, those with variants only at GRK4486V were less likely to achieve the BP goal in response to an ARB than those with no variants. These studies showed for the first time the association between GRK4142V and a larger decrease in BP with ARBs in hypertensive patients.