Circulating 25-hydroxyvitamin D (25(OH)D) has been associated with cardiovascular disease (CVD) risk inobservational studies. Also, SNPs to explain variation in 25(OH)D have been identified by genome-wide associationstudies. Detection of direct associations between SNPs that significantly affect 25(OH)D and CVD risk would indicatea causal role of vitamin D, as reverse causation could be excluded and confounding could be better controlled. Thus,a combined analysis of candidate SNPs in relation to circulating 25(OH)D and CVD risk was carried out. A casecohort study within the EPIC-Germany study was conducted comprising a randomly drawn subcohort of 2,132subjects (57.9% women, mean age: 50.6 years) and incident cases of myocardial infarction (n=559) and stroke(n=471) that occurred during a mean follow-up duration of 7.6 years. 25(OH)D concentrations were measured by LCMS/MS in baseline plasma samples. Additionally, eight candidate SNPs were assayed. Associations between25(OH)D, SNPs and the risks of myocardial infarction and stroke were assessed by multivariable regressionanalyses. Mean 25(OH)D level was 47.2 nmol/L in the subcohort. Four SNPs were associated with 25(OH)D(p<0.05). In subjects with 25(OH)D levels <25 nmol/L, the risks of CVD as composite endpoint (Hazard Ratio: 1.53,95% confidence interval: 1.12–2.09), myocardial infarction, and stroke were significantly increased compared tosubjects with levels ≥50 nmol/L, while no significant linear associations were observed. A SNP score was not relatedto the risks of total CVD (Hazard Ratio: 1.0, 95% confidence interval: 0.71–1.42), myocardial infarction, or stroke. Thesame was true concerning single SNPs. Given the lack of association between SNPs and the risks of stroke andmyocardial infarction, the present findings do not point to a major causal role of vitamin D in the development ofthese diseases. However, a detection of modest associations between genetic markers and CVD risk in largerconsortia cannot be ruled out.