AIM: Evidence for the effect of elevated blood pressure on the risk of venous thromboembolism (VTE) has been conflicting. We sought to assess the association between systolic blood pressure and the risk of VTE. METHODS AND RESULTS: Three complementary studies comprising an observational cohort analysis, a one-sample and two-sample Mendelian randomization were conducted using data from 5,588,280 patients registered in the Clinical Practice Research Datalink (CPRD) dataset and 432,173 UK Biobank participants with valid genetic data. Summary statistics of International Network on Venous Thrombosis (INVENT) genome-wide association meta-analysis was used for two-sample Mendelian randomization. The primary outcome was the first occurrence of VTE event, identified from hospital discharge reports, death registers, and/or primary care records. In the CPRD cohort, 104,017 (1.9%) patients had a first diagnosis of VTE during the 9.6-year follow-up. Each 20 mmHg increase in systolic blood pressure was associated with a 7% lower risk of VTE (hazard ratio 0.93, 95% CI [0.92 to 0.94]). Statistically significant interactions were found for sex and body mass index, but not for age and subtype of VTE (pulmonary embolism and deep venous thrombosis). Mendelian randomization studies provided strong evidence for the association between systolic blood pressure and VTE, both in the one-sample (odds ratio [OR]: 0.69 [95% CI 0.57 to 0.83] and two-sample analyses (OR 0.80, 95% CI [0.70 to 0.92]). CONCLUSIONS: We found an increased risk of VTE with lower blood pressure and this association was independently confirmed in two Mendelian randomization analyses. The benefits of blood pressure reduction are likely to outweigh the harms in most patient groups, but in people with predisposing factors for VTE, further blood pressure reduction should be made cautiously. TRANSLATIONAL PERSPECTIVE: In a large-scale population cohort, with over 100,000 first episodes of VTE and a median follow-up of about 10 years, we found a 7% higher risk of VTE for each 20 mmHg lower systolic blood pressure. The association was comparable when we examined pulmonary embolism and deep venous thrombosis separately, and persisted after taking into account age and other factors, including anticoagulant treatment during follow-up. These results were confirmed using two independent Mendelian randomization studies. Although the beneficial effects of blood pressure-lowering are likely to outweigh any harms in most patient groups, clinicians should be aware of the potential risk of VTE from antihypertensive therapy, in particular in people who have predisposing factors for VTE.