During atherosclerosis, leukocytes infiltrate the vessel wall and release myeloperoxidase, which forms hypochlorous acid (HOCl). HOCl is highly reactive and forms chlorinated DNA and RNA products that are present within atherosclerotic plaques. In this study, the effect of various chlorinated nucleoside products on endothelial and smooth muscle cell function was examined, as these cells are dysregulated in atherosclerosis. Human coronary artery endothelial cells (HCAEC) and human coronary artery smooth muscle cells (HCASMC) were exposed to different chlorinated nucleosides. 8-chloroadenosine (8ClA) was readily incorporated into the RNA and nucleotide pool, resulting in the accumulation of 8ClATP. In HCAEC, 8ClA activated the unfolded protein response leading to cytosolic calcium accumulation, altered cellular respiration and apoptotic cell death. 8ClA affected the proliferation rate of HCASMC but did not activate the unfolded protein response. HCASMC are more susceptible to 5-chorodeoxycytidine (5CldC), with exposure to this nucleoside activating inflammatory pathways, which culminates in elevated matrix metalloproteinase expression. These data support a role of chlorinated nucleosides in promoting vascular cell dysfunction in atherosclerosis.