Antihypertensive therapy is pivotal in preventing cardiovascular events, yet treatment efficacy varies significantly among individuals due to genetic polymorphisms.This study aimed to investigate the association between specific antihypertensive drug-related gene polymorphisms, the use of corresponding sensitive drugs, and the risks of stroke and coronary heart disease (CHD) in a community-based hypertensive population. A cross-sectional study was conducted among 29,662 hypertensive patients from primary care centers in Changsha County, China. Seven gene loci (ACE(I/D), CYP2C9*3,AGTR1(1166 A > C), CYP2D6*10,ADRB1(1165G > C), CYP3A5*3, and NPPA(2238T > C))were genotyped.Patients were stratified into sensitive or non-sensitive genotype groups. Logistic regression and interaction analysis were employed to assess gene-drug interactions on cardiovascular outcomes. The prevalence of stroke and CHD was 2.8% and 19.5%, respectively. Carriers of sensitive genotypes for AGTR1, CYP2D6*10, and ADRB1 taking sensitive drugs exhibited a significantly lower risk of stroke (ORs: 0.39, 0.67, 0.68; all P < 0.01). Similarly, sensitive genotype carriers for CYP2D6*10, CYP3A5*3, and NPPA taking sensitive drugs had a reduced risk of CHD (ORs: 0.92, 0.88, 0.53; all P < 0.05). A significant additive interaction was identified between AGTR1(1166 A > C) and sensitive drug use on CHD risk (AP = 0.08). Pharmacogenomics-guided antihypertensive therapy is associated with a reduced risk of stroke and CHD in hypertensive patients. The interaction between AGTR1(1166 A > C) genotype and drug use underscores the potential of personalized medicine in optimizing cardiovascular disease prevention strategies in primary care.