BackgroundAssociations between blood pressure (BP) with age at onset of Huntington’s disease (HD) have reported inconsistent findings. We used Mendelian randomization (MR) to assess effects of BP and lowering systolic BP (SBP) via the genes encoding targets of antihypertensive drugs on age at onset of HD.MethodsGenetic variants from genome-wide association studies(GWAS) of BP traits and BP-lowering variants in genes encoding antihypertensive drugs targets were extracted. Summary statistics for age at onset of HD were retrieved from the GWAS meta-analysis of HD residual age at onset from the GEM-HD Consortium included 9064 HD patients of European ancestry (4417 males and 4,647 females). MR estimates were calculated using the inverse variance weighted method, supplemented by MR-Egger, weighted median, and MR-PRESSO methods.ResultsGenetically predicted SBP or diastolic BP increase was associated with a later age at onset of HD. However, after SBP/DBP was present as a covariate using multivariable MR method, no significant causal association was suggested. A 10-mm Hg reduction in SBP through variants in genes encoding targets of calcium channel blockers (CCB) was associated with an earlier age at onset of HD (β=-0.220 years, 95% CI =-0.337 to -0.102, P = 2.42 × 10− 4). We did not find a causal association between angiotensin converting enzyme inhibitors and β-blockers with the earlier HD onset. No heterogeneity and horizontal pleiotropy were identified.ConclusionsThis MR analysis provided evidence that genetically determined SBP lowering through antihypertensive drugs might be associated with an earlier age at onset of HD. The results may have a potential impact on management of hypertension in the pre-motor-manifest HD population.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13023-023-02734-1.