Observational studies indicate that low concentrations of plasma 25-hydroxyvitamin D (25(OH)D) are associated with high blood pressure, hypertension, and ischemic stroke. However, whether these associations are causal remain unknown. A total of 116 655 white individuals of Danish descent from the general population were genotyped for genetic variants in DHCR7 and CYP2R1 affecting plasma 25(OH)D concentrations; 35 517 had plasma 25(OH)D measurements. Primary outcomes were blood pressure, hypertension, and ischemic stroke. Median follow-up for incident ischemic stroke was 9.3 years (range, 1 day-33.6 years). DHCR7/CYP2R1 allele score was as expected associated with lower 25(OH)D concentration (F=328 and R(2)=1.0%). A genetically determined 10 nmol/L lower 25(OH)D concentration was associated with a 0.68 (95% confidence interval [CI], 0.20-1.17) mm Hg higher systolic blood pressure and a 0.36 (95% CI, 0.08-0.63) mm Hg higher diastolic blood pressure with corresponding observational estimates of 0.58 (95% CI, 0.50-0.68) and 0.40 (95% CI, 0.35-0.45) mm Hg. The odds ratio for hypertension was 1.02 (95% CI, 0.97-1.08) for a genetically determined 10 nmol/L lower 25(OH)D with a corresponding observational odds ratio of 1.06 (95% CI, 1.05-1.07). The odds ratio for ischemic stroke was 0.98 (95% CI, 0.86-1.13) for a genetically determined 10 nmol/L decrease in 25(OH)D with a corresponding observational odds ratio of 1.03 (95% CI, 1.01-1.05). Genetic and observational low 25(OH)D concentrations were associated with higher blood pressure, as well as with hypertension consistent with causal relationships. Because observational but not genetic low 25(OH)D concentration was associated with ischemic stroke, and as the CIs overlapped, we can neither support nor exclude a causal relationship.