Abstract: AIM:To investigate the effects of cellular repressor of E1A-stimulated genes (CREG) on atherosclerotic lesion formation. METHODS: Western blot was used to detect the expression of CREG in human normal and atherosclerotic arteries from amputation surgery. The morphology of the artery and expression of CREG, smooth muscle α-actin （SMα-actin）and smooth muscle-myosin heavy chain (SM-MHC) on natural atherosclerotic formation were observed in rabbits fed a high-fat diet. RESULTS: In human atherosclerotic artery, the expression of CREG decreased significantly in atherosclerotic artery, accompanied by the decrease of SMα-actin. In rabbit models fed a high-fat diet for 1 month, the endothelium was not smooth and the intima became thicker. The phenotype of vascular smooth muscle cells (VSMCs) changed. Expression of CREG, SMα-actin and SM-MHC decreased and VSMCs proliferated. In rabbit models fed a high-fat diet for 2 months, the endothelium discontinued and the intima became thicker. The number of proliferating cell nuclear antigen (PCNA) positive cells was much higher and the levels of CREG, SMα-actin and SM-MHC protein were lower in VSMCs. CONCLUSION: The phenotype of VSMCs changes from differentiation to synthesis in atherosclerotic formation. CREG expression decreases with the development of atherosclerosis, suggesting that CREG is associated with atherosclerosis.