BACKGROUND: In medicine, clinicians treat individuals under an implicit assumption that high-risk patients would benefit most from the treatment (high-risk approach). However, treating individuals with the highest estimated benefit using a novel machine-learning method (high-benefit approach) may improve population health outcomes. METHODS: This study included 10 672 participants who were randomized to systolic blood pressure (SBP) target of either <120 mmHg (intensive treatment) or <140 mmHg (standard treatment) from two randomized controlled trials (Systolic Blood Pressure Intervention Trial, and Action to Control Cardiovascular Risk in Diabetes Blood Pressure). We applied the machine-learning causal forest to develop a prediction model of individualized treatment effect (ITE) of intensive SBP control on the reduction in cardiovascular outcomes at 3 years. We then compared the performance of high-benefit approach (treating individuals with ITE >0) versus the high-risk approach (treating individuals with SBP ≥130 mmHg). Using transportability formula, we also estimated the effect of these approaches among 14 575 US adults from National Health and Nutrition Examination Surveys (NHANES) 1999-2018. RESULTS: We found that 78.9% of individuals with SBP ≥130 mmHg benefited from the intensive SBP control. The high-benefit approach outperformed the high-risk approach [average treatment effect (95% CI), +9.36 (8.33-10.44) vs +1.65 (0.36-2.84) percentage point; difference between these two approaches, +7.71 (6.79-8.67) percentage points, P-value <0.001]. The results were consistent when we transported the results to the NHANES data. CONCLUSIONS: The machine-learning-based high-benefit approach outperformed the high-risk approach with a larger treatment effect. These findings indicate that the high-benefit approach has the potential to maximize the effectiveness of treatment rather than the conventional high-risk approach, which needs to be validated in future research.