To examine whether previous observed inverse associations of dairy intake with systolic blood pressure and risk of hypertension were causal. Mendelian randomization study using the single nucleotide polymorphism rs4988235 related to lactase persistence as an instrumental variable. CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium. Data from 22 studies with 171 213 participants, and an additional 10 published prospective studies with 26 119 participants included in the observational analysis. The instrumental variable estimation was conducted using the ratio of coefficients approach. Using meta-analysis, an additional eight published randomized clinical trials on the association of dairy consumption with systolic blood pressure were summarized. Compared with the CC genotype (CC is associated with complete lactase deficiency), the CT/TT genotype (TT is associated with lactose persistence, and CT is associated with certain lactase deficiency) of (lactase persistence gene) rs4988235 was associated with higher dairy consumption (0.23 (about 55 g/day), 95% confidence interval 0.17 to 0.29) serving/day; P<0.001) and was not associated with systolic blood pressure (0.31, 95% confidence interval -0.05 to 0.68 mm Hg; P=0.09) or risk of hypertension (odds ratio 1.01, 95% confidence interval 0.97 to 1.05; P=0.27). Using rs4988235 as the instrumental variable, genetically determined dairy consumption was not associated with systolic blood pressure (β=1.35, 95% confidence interval -0.28 to 2.97 mm Hg for each serving/day) or risk of hypertension (odds ratio 1.04, 0.88 to 1.24). Moreover, meta-analysis of the published clinical trials showed that higher dairy intake has no significant effect on change in systolic blood pressure for interventions over one month to 12 months (intervention compared with control groups: β=-0.21, 95% confidence interval -0.98 to 0.57 mm Hg). In observational analysis, each serving/day increase in dairy consumption was associated with -0.11 (95% confidence interval -0.20 to -0.02 mm Hg; P=0.02) lower systolic blood pressure but not risk of hypertension (odds ratio 0.98, 0.97 to 1.00; P=0.11). The weak inverse association between dairy intake and systolic blood pressure in observational studies was not supported by a comprehensive instrumental variable analysis and systematic review of existing clinical trials.