Coronary artery disease (CAD) is a progressive cardiovascular syndrome characterized by cholesterol-induced focal arterial lesions that impair oxygen delivery to the heart. As both innate and adaptive immune cells play critical roles in the formation and progression of arterial plaques and endothelial cell dysfunction, CAD is commonly viewed as a chronic inflammatory disorder. Our lab has previously discovered that 5-HT2A receptor activation with the 5-HT2 receptor selective agonist (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI] has potent anti-inflammatory activity in both cell culture and whole animal models. Here we have examined the putative therapeutic effects of (R)-DOI in the ApoE-/- high fat model of cardiovascular disease. Subcutaneously implanted osmotic minipumps were used to infuse sustained low rates (0.15 μg / hr) of (R)-DOI∙HCl to mice fed a high-fat "Western" diet. (R)-DOI treated mice had significant reductions in expression levels of mRNA for inflammatory markers like Il6 in vascular tissue, normalized glucose homeostasis, and reduced circulating cholesterol levels. As cardiovascular disease is a leading cause of death both globally and in the Western world, activation of 5-HT2A receptors at sub-behavioral levels may represent a new strategy to treat inflammation-based cardiovascular disease.