Vitamin D is not only a secosteroid important for calcium homeostasis, ever increasing data also points to its role in regulating immune responses. It is also well-established that vitamin D impacts gene regulation via vitamin D response elements (VDREs) across the genome. Recent evidence, primarily generated in cell lines at a locus-specific level, suggests that alterations to DNA methylation may also be a relevant mechanism through which vitamin D regulates gene expression. Given the intense interest in vitamin D, particularly as an immune modifier, we sought to examine the impact of vitamin D exposure on the immune cell methylome in vitro. We exposed primary human blood mononuclear cells (PBMCs) with up to 100 nM calcitriol for up to 120 hours, and measured genome-scale DNA methylation response using the Illumina Infinium HumanMethylation450 beadchip array. We observed that, while the expression of known vitamin D responsive genes was clearly altered by calcitriol exposure, substantial genome-scale changes to DNA methylation were not induced. Cluster analysis of beta methylation values, either genome-wide or restricted to the top 5000 most variable probes, did not suggest a dose-dependent relationship between samples. This is the first study to directly explore the effect of vitamin D on primary immune cell DNA methylation on a genome scale, and our data suggests that changes to DNA methylation may not be a predominant mechanism through which vitamin D impacts gene expression in such cells.