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To explore the association between polymorphism in the ACE I/D gene and blood pressure-lowering response to hydrochlorothiazide (HCTZ) in 829 patients. Methods HCTZ 12.5 mg was taken once a day for six weeks. The blood pressure reduction and ratio reaching target blood pressure were compared in different ACE genotype groups. Results The reduction in SBP of patients carrying DD was greater than that in other groups carrying Ⅱ or ID (12.2 mmHg versus 5.4 mmHg,12.2 mmHg versus 4.4 mmHg, respectively, P＜0.05). The reduction in MAP of patients carrying DD was also greater than that in other groups carrying Ⅱ or ID (6.9 mmHg versus 3.9 mmHg, 6.9 mmHg versus 3.6 mmHg, respectively, P＜0.05). The ratio reaching target blood pressure in DD groups was significantly higher than that in Ⅱ or ID groups (P＜0.05). The pre-treatment SBP, DD genotype, aldosterone levels entered the multi-linear regression model significantly and might affect the reduction of SBP. The pre-treatment DBP, aldosterone levels, DD genotype entered the multi-linear regression model significantly and might affect the reduction of DBP. The pre-treatment MAP, DD genotype, aldosterone levels entered the multi-linear regression model significantly and might affect the reduction of MAP. Conclusion ACE genotyping is associated with blood pressure-lowering response to HCTZ. Specific genotypes might be associated with the response to specific antihypertensive treatment.