Atherosclerosis, the leading cause of morbidity and mortality of cardiovascular disease, occur due to hardening and narrowing of arteries for development of vulnerable plaques made of cholesterols, tissue macrophages, foam cells and smooth muscle cells. Early detection of atherosclerosis is essential for proper treatment. Our group has already reported about the potential application of the non-invasive diffusion reflection (DR) technique in the detection of atherosclerosis using gold nanorods (GNRs) as contrast agent in carotid artery injured mice model. The basics of the study lie on the uptake GNRs by macrophages that located at the vulnerable plaques, which act as a good absorption contrast for DR measurement. Accumulations of GNRs cause changes in the optical property of the tissues and in turn cause changes in DR profile. In this study, we report the potential application of DR measurement in the detection of atherosclerosis in high-fat diet mice. Here, we have used PEG-coated GNRs with absorption maxima around 660nm. The time kinetics showed that after 24h of GNR injection the DR can find the atherosclerotic plaques and with time (up to 72h) the GNR accumulation in plaques were faded out, but still can be detectable by DR. Our result strongly suggests that in future DR can be used for early detection of atherosclerosis.