Objective To explore the underlying molecular mechanisms of estrogen induced apoptosis of synthetic vascular smooth muscle cells (VSMCs). Methods Cultured VSMCs on passage 3 were divided into three groups: 17β-estradiol (E\-2) group, p38 inhibitor group (SB+E\-2) and control group. With treatment for 72 hours,the apoptosis of cells was quantified by measuring the intracellular nucleosomes with ELISA; expressions of total p38, phospho-p38 and myocyte enhancer factor2 (MEF2) were analyzed by Western blotting, with a confirmative immunohistochemical staining for MEF2. Results Compared with that of control cells, the rate of apoptosis in VSMCs grown in E\-2 was significantly increased, with upregulations of total p38, phosphop38 and MEF2. These effects of E\-2 were blocked in SB+E\-2 group in which the rate of cell apoptosis and expression of p38 had no obvious change compared with that of control group, while the expression of p-p38 and MEF2 was decreased. Immunohistochemical staining showed that MEF2 was mainly located in cellular nucleus, and its expression was increased in E\-2 group but decreased in SB+E\-2 group. Conclusion Estrogen may induce apoptosis of synthetic VSMCs