Recent experimental and clinical studies suggested that apart from playing an essential role in blood pressure homeostasis, aldosterone is involved in the pathophysiology of cardiovascular and renal diseases by inducing structural changes in the heart, kidney, and vessel wall. The interindividual variation of aldosterone response to antihypertensive treatment is considerable, and is at least partially explained by genetic variation. In this study, we investigated aldosterone response to two antihypertensive drugs-a thiazide diuretic and an angiotensin receptor blocker (ARB). Genetic variations in 50 candidate genes were tested for association with aldosterone response in four independent samples: African American (AA) responders to a diuretic (n = 289), AA responders to an ARB (n = 252), European American (EA) responders to a diuretic (n = 295) and EA responders to an ARB (n = 300). Linear regression was used to test the association with inclusion of age, sex, and body mass index as covariates. The results indicated the existence of one or more variants in the kininogen gene (KNG) that influence interindividual variation in aldosterone response. The significant association was replicated in three of four studied groups. The single nucleotide polymorphism rs4686799 was associated in AA and EA responders to the diuretic (P = 0.04 and P = 0.07, respectively), and rs5030062 and rs698078 were significantly associated in EA responders to the diuretic (P = 0.05 and P = 0.01) and EA responders to the ARB (P = 0.04 and P = 0.02). Although the clinical implication of KNG gene variation to antihypertensive drug response is yet to be determined, this novel candidate locus provides important new insights into drug response physiology.