A cluster study of 438 hypertensive patients across nine Amsterdam practices found that targeted guidance promoting single-pill combination (SPC) therapy achieved superior blood pressure reductions. The intervention group experienced 15.7 mmHg systolic and 6.9 mmHg diastolic decreases compared to 10.4/4.6 mmHg in usual care. SPC initiation rates jumped from 9.6% to 25.1% with guidance, and target blood pressure achievement improved from 48.1% to 57.3%. Among actual SPC users, reductions reached 22.4/10.5 mmHg. This targeted approach addresses a persistent clinical challenge in hypertension management. Despite decades of effective medications, blood pressure control remains suboptimal globally, particularly in disadvantaged communities where medication adherence barriers are highest. The findings reinforce cardiovascular guidelines recommending combination therapy as first-line treatment, though the modest absolute improvement in target achievement suggests implementation barriers persist. The study's focus on a multi-ethnic, socially disadvantaged population adds valuable real-world evidence, though the quasi-randomized design and relatively short follow-up limit causal inferences. As a preprint awaiting peer review, these promising results require validation, but they support pragmatic, practice-level interventions to optimize hypertension care in vulnerable populations.