Aim: This study was conducted to demonstrate the anti-atherosclerotic effect of dehydroepiandrosterone (DHEA) and to investigate its possible mechanisms and whether this effect is related to its conversion to estrogen.Methods: Forty male New Zealand White rabbits aged 3 months were divided into 5 groups (n=8 per group) and fed dif-ferent diets for 10 weeks. Serum lipid levels, the area of atherosclerotic lesions and the mRNA levels of monocyte chemoat-tractant protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) in aortic lesions were measured. Then cultured vascular smooth muscle cells (VSMCs) stimulated by oxidized low density lipoprotein-cholesterol (ox-LDL) were treated by DHEA. The gene and protein expression levels of MCP-1 and VCAM-1 in VSMCs was detected. The plasmid with or with-out the gene of cytochrome P450 aromatase (CYP19) was transient transfected into cultured VSMCs respectively. Twenty hours later, the cells were stimulated with ox-LDL and DHEA.Results: DHEA could obviously decrease the area of atherosclerotic lesions and the expressions of MCP-1 and VCAM-1 in aortic lesions. But all-trans retinoic acid (atRA) which was reported would limit restenosis after balloon angioplasty had no visible synergistic effect with DHEA. DHEA could also reduce ox-LDL-induced MCP-1 and VCAM-1 expression in un-transfected or transfected VSMCs.Conclusion: The anti-atherosclerotic effect of DHEA had nothing to do with the catalysis of cytochrome P450 aromatase (CYP19), or was not related to its conversion to estrogen.