Importance Hypertension is the leading risk factor for premature death worldwide. Multiple blood pressure–lowering therapies are available but the potential for maximizing benefit by personalized targeting of drug classes is unknown.

Objective To investigate and quantify the potential for targeting specific drugs to specific individuals to maximize blood pressure effects.

Design, Setting, and Participants A randomized, double-blind, repeated crossover trial in men and women with grade 1 hypertension at low risk for cardiovascular events at an outpatient research clinic in Sweden. Mixed-effects models were used to assess the extent to which individuals responded better to one treatment than another and to estimate the additional blood pressure lowering achievable by personalized treatment.

Interventions Each participant was scheduled for treatment in random order with 4 different classes of blood pressure–lowering drugs (lisinopril [angiotensin-converting enzyme inhibitor], candesartan [angiotensin-receptor blocker], hydrochlorothiazide [thiazide], and amlodipine [calcium channel blocker]), with repeated treatments for 2 classes.

Main Outcomes and Measures Ambulatory daytime systolic blood pressure, measured at the end of each treatment period.

Results There were 1468 completed treatment periods (median length, 56 days) recorded in 270 of the 280 randomized participants (54% men; mean age, 64 years). The blood pressure response to different treatments varied considerably between individuals (P < .001), specifically for the choices of lisinopril vs hydrochlorothiazide, lisinopril vs amlodipine, candesartan vs hydrochlorothiazide, and candesartan vs amlodipine. Large differences were excluded for the choices of lisinopril vs candesartan and hydrochlorothiazide vs amlodipine. On average, personalized treatment had the potential to provide an additional 4.4 mm Hg–lower systolic blood pressure.

Conclusions and Relevance These data reveal substantial heterogeneity in blood pressure response to drug therapy for hypertension, findings that may have implications for personalized therapy.

Trial Registration ClinicalTrials.gov Identifier: NCT02774460