Technical Abstract: Vitamin D receptors have a broad tissue distribution that includes vascular smooth muscle, endothelium, and cardiomyocytes. A growing body of evidence suggests that vitamin D deficiency may adversely affect the cardiovascular system, but few prospective data exist. This study examined the relation of vitamin D status, assessed using 25-dihydroxyvitamin-D (25-OH D) levels, to the incidence of first cardiovascular events in 1739 Framingham Heart Study participants (mean age 59 years, 55% women). Pre-specified thresholds were used for moderate (10 to <15 ng/ml) and severe (<10 ng/ml) vitamin D deficiency. Multivariable Cox regression models were adjusted for conventional risk factors and renal function. The results showed that the prevalence of vitamin D deficiency (25-OH D <15 ng/ml) was 28%. During a mean follow-up of 5.4 years, 120 individuals developed a first cardiovascular event. Overall, vitamin D deficiency was associated with a multivariable-adjusted hazards ratio of 1.62 (95% confidence interval {CI}, 1.11-2.36; p=0.001) for incident cardiovascular events. Moderate and severe vitamin D deficiency were associated with multivariable-adjusted hazards ratios of 1.53 (95% CI, 1.00-2.36) and 1.80 (95% CI, 1.05-3.08), respectively. The excess risk was particularly prominent in hypertensive individuals, who had multivariable-adjusted hazards ratios of 1.93 (95% CI, 1.09-3.42) for moderate and 2.51 (95% CI, 1.30-4.82) for severe vitamin D deficiency. The findings show that vitamin D is associated with increased risk of developing cardiovascular disease, which may have public health implications, given the high prevalence of vitamin D deficiency, the contribution of lifestyle to vitamin D status, and the ease and low cost of repletion.