Background and aims Reducing the diastolic blood pressure (DBP) below a certain threshold may lead to inadequate organ perfusion. This raises some concerns, because pharmacotherapy reduces both systolic and diastolic pressure. We aimed to investigate whether a pathway from intensive systolic blood pressure (SBP) treatment influences cardiovascular outcomes by inducing too low DBP. Methods We had access to data from the Systolic Blood Pressure Intervention Trial (SPRINT) including 9361 patients with a SBP of 130 mmHg or higher and an increased cardiovascular risk. In a formal mediation analysis, we investigated whether the effect of intense (target SBP: 120 mm Hg) vs. standard (target SBP: 140 mmHg) intervention on a composite endpoint would be mediated through an indirect, potentially harmful, effect through low DBP (< 60 mmHg). Results Adjusting for treatment, we find that low DBP per se is associated with poor cardiovascular outcomes (HR 1.90 (95% CI [1.46, 2.47]). However, in a formal mediation analyses, we observed that the unadjusted indirect effect of intensive blood pressure treatment going through low DBP of HR 1.12 (95% CI [1.06, 1.18]) attenuates to a statistically non-significant effect of HR 1.04 (95% CI [0.98, 1.10]) after adjustment for important covariates, suggesting that the mere association is considerably confounded. Conclusions The increased risk in subjects with diastolic pressure below 60 cannot fully be explained by the intensive treatment itself, but may be due to other measured factors. More generally, this analysis shows that adjusting for mediator-outcome confounding is essential, even in RCTs.