Despite the availability of effective antihypertensive drugs, there is a large variation in response to these drugs. This study investigates whether polymorphisms in the angiotensin converting enzyme (I/D), angiotensinogen (M235T), alpha-adducin (G460W), angiotensin II type 1 receptor (1166A/C), or G protein beta(3)-subunit (825C/T) gene modify the mean difference in blood pressure levels among diuretics, beta-blockers, or ACE-inhibitors users. Data were used from the Doetinchem Cohort Study, and blood pressure data were collected from GPs (1987-1997). A marginal generalized linear model (GEE) was used to assess the gene-drug interaction on the mean difference in systolic/diastolic blood pressure. In total, 625 hypertensive individuals were included with a total of 5262 measurements of blood pressure. Only the interaction between diuretic use and the GNB3 825C/T polymorphism was significant (C allele versus TT systolic blood pressure (SBP): 4.33 mmHg [95% CI: 0.14-8.54]). Thus, the mean SBP level among diuretic users may be modified by the GNB3 825C/T polymorphism.