Background The SPRINT trial showed a beneficial effect of systolic blood pressure treatment targets of 120 mmHg on cardiovascular risk compared to targets of 140 mmHg. However, differences in medication use, most importantly diuretics, are suggested as an alternative explanation. This post-hoc analysis aimed to determine whether the reduced event rate can be attributed to changes in systolic blood pressure (ΔSBP) . Methods Analyses were based on all 9361 participants of the SPRINT trial. ΔSBP was defined as the change between baseline and 6-month follow-up systolic blood pressure. Major cardiovascular events were myocardial infarction, other acute coronary syndromes, stroke, heart failure, or cardiovascular death. Cox regression was used to describe the relation between ΔSBP and major cardiovascular events. Analyses were performed separately for patients in the lowest tertile of baseline systolic blood pressure, as the SPRINT trial reported the highest treatment effect in this subgroup. Results The relation between ΔSBP and major cardiovascular events was a hazard ratio per 10 mmHg decrease of 0.93 (95% confidence interval 0.89-0.98). Similar results were found within the lowest tertile of baseline systolic blood pressure: hazard ratio per 10 mmHg decrease 0.91 (95% confidence interval 0.82-1.01). Conclusion Our results show that lowering blood pressure prevents cardiovascular disease. However, not all the positive effects in the SPRINT trial could be explained by ΔSBP. Alternative explanations, such as differences in medication use, should be considered for the positive findings of the SPRINT trial.