Abstract: Objective To determine the correlation of antihypertensive effects of hydrochlorothiazide with polymorphism of ACE and α-adducin genes. Methods Antihypertensive response to HCTZ 12.5mg once daily for 6 weeks were assessed in 829 patients with mild or moderate hypertension. ACE I/D and α-adducin G614T genotypes were determined in patients. Results Of 754 patients completed the study, the decrease in SBP of patients carrying DD of ACE gene was significantly greater than that in those with Ⅱ or ID（P＜0.05）. The decrease in SBP was significantly greater in patients with the TT genotype of α-adducin G614T as compared with GT or GG genotype（P＜0.01）. Patients carrying 614T allele of α-adducin had the greatest DBP decrease after treatment （P＜0.01）. Multivariate stepwise regression analysis revealed that the DD genotype, TT genotype, the combination of the 2 genotypes, and the baseline aldosterone were the major determinants for the decreases in SBP. Conclusion The data suggests that the polymorphism of ACE I/D and α-adducin G614T might be associated with antihypertensive effect of HCTZ especially in the individuals with combination of DD+TT genotypes.