Objective: To investigate the effect of norepinephrine (NE) on the proliferation and phenotypic transformation of vascular smooth muscle cells (VSMCs) and the mechanisms underlying this effect. Methods: VSMCs were isolated from the rat abdominal aorta. VSMCs cultured in both serum-containing or in a serum-free medium were treated with NE, oxidized low-density lipoprotein (ox-LDL), α-adrenergic receptor agonist (α1-R−), β1-adrenergic receptor antagonist (β1-R−) and various combinations of these factors. VSMC proliferation was determined by bromodeoxyuridine (BrdU) assays. The mRNA expression level of HRG-1 and SM22α were determined by reverse transcription-polymerase chain reaction (RT-PCR). Results: The expressions of HRG-1 and SM22α mRNA in NE-or OX-LDL-treated VSMCs was down-regulated, and the proliferation of BrdU-labeled cells increased; the expression of the abovementioned genes in the VSMCs treated with a combination of NE, α1-R, and β1-R was significantly up-regulated. However, NE was observed to up-regulate the expression of HRG-1 and SM22α mRNA in serum-starved VSMCs. Conclusion: NE could reversibly regulate the proliferation and phenotypic transformation of VSMCs. This regulation might be mediated via its receptors.