BACKGROUND The success of anti hypertensive drugs may be improved by better prediction of their efficacy in individual patients. The objective of our study was to determine whether genetic variation predicts the individual systolic blood pressure (SBP) response to anti hypertensive drugs and to assess to what extent the individual treatment response could be explained by the combined effects of known demographic, environmental, and genetic factors. METHODS A population-based, crossover, open-label randomized treatment study stratified for ethnicity in 102 mildly hypertensive patients aged 35-60 years in an outpatient hypertension clinic (the ROTATE study). Patients underwent five successive 6-week treatment episodes of single-drug treatment in a randomized order with representatives of the major anti hypertensive drug classes. The primary outcome measure was the ASBP after 6-week drug therapy. RESULTS Participants (n = 97) completed 407 treatment episodes. The estimated unpredictable natural variation of SBP within individuals was 65% of the total study variance. The primary analysis model that considered the effects of environmental, demographic, and genetic factors and their interactions to SBP response to antihypertensive drugs, explained 23% of the total variance accounting for 66% of the predictable variance. Ethnicity, low sodium intake, and ADD1 614G -> T polymorphism were the only drug-related predictors. A number of genetic variants (ADD1 614G -> T, ADRB1 145A -> G, ADRB2 79C -> G, CYP11B2-344C -> T, and SLC12A3 78G -> A) contributed significantly (9%) to the total variance of the SBP response. The contribution of each individual single-nucleotide polymorphism (SNP) ranged from 1.1 to 2.4%. CONCLUSIONS Genetic factors are relevant and independent determinants of anti hypertensive drug effects in a multiracial population.